Acyl-benzimidazole-2-methanol derivatives

ABSTRACT

New heterocyclylcarboxylic acid derivatives which are acylated in the nucleus, especially benz-acyl-benzimidazole-2-carboxylic acid derivatives of the formula ##STR1## in which R is a free, esterified or amidated carboxyl group or a free, etherified or esterified hydroxymethyl group, R 1  is an aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic or heterocyclic-aliphatic radical, R 2  is hydrogen or an aliphatic radical and Ph is a 1,2-phenylene group containing the radical R 1  --C(═O)--, with the proviso that R 1  contains at least 2 carbon atoms if Ph is otherwise unsubstituted, R 2  is ethyl and R is acetoxymethyl, and salts of such compounds having salt-forming properties, are useful as anti-allergic agents.

This is a division of application Ser. No. 825,630, filed on Aug. 18,1977 now U.S. Pat. No. 4,141,982.

The invention relates to processes for the preparation ofheterocyclylcarboxylic acid derivatives which are acylated in thenucleus, especially benz-acyl-benzimidazole-2-carboxylic acidderivatives of the formula ##STR2## in which R is a free, esterified oramidated carboxyl group or a free, etherified or esterifiedhydroxymethyl group, R₁ is an aliphatic, cycloaliphatic, aromatic,araliphatic, heterocyclic or heterocyclic-aliphatic radical, R₂ ishydrogen or an aliphatic radical and pH is a 1,2-phenylene groupcontaining the radical R₁ --C(═O)--, with the proviso that R₁ containsat least 2 carbon atoms if Ph is otherwise unsubstituted, R₂ is ethyland R is acetoxymethyl, and salts of such compounds having salt-formingproperties, and also the compounds of the formula I and salts of suchcompounds having salt-forming properties, and also pharmaceuticalformulations containing such compounds and the use of the latter aspharmaceuticals.

In the context of the present description, organic radicals andcompounds designated as "lower" contain, especially, up to and including7 and preferably up to and including 4 carbon atoms.

In esterified carboxyl and etherified hydroxymethyl R, the etherifiedhydroxyl group is, for example, a hydroxyl group etherified by analiphatic or araliphatic radical, such as a substituted or unsubstitutedaliphatic or araliphatic hydrocarbon radical, for example correspondinglower alkoxy or phenyl-lower alkoxy. Substituents of lower alkoxy are,inter alia, hydroxyl, lower alkoxy and/or di-lower alkyl-amino, andthose of phenyl-lower alkoxy are, for example, lower alkyl, lower alkoxyand/or halogen, it being possible for one or more substituents to bepresent.

In amidated carboxyl, the amino group is, for example, amino which isunsubstituted or monosubstituted by hydroxyl or monosubstituted ordisubstituted by aliphatic radicals, especially by substituted orunsubstituted aliphatic hydrocarbon radicals, it being possible for suchradicals to be monovalent or divalent, such as amino which isunsubstituted or monosubstituted by hydroxyl or monosubstituted ordisubstituted by corresponding lower alkyl or lower alkylene.

In esterified hydroxymethyl R, the esterified hydroxyl group is, forexample, hydroxyl esterified by a carboxylic acid, such as an aliphaticor aromatic carboxylic acid, for example corresponding lower alkanoyloxyor benzoyloxy which is unsubstituted or substituted by lower alkyl,lower alkoxy and/or halogen. Lower alkanoyloxy is, for example, acetoxy,propionyloxy, butyryloxy, isobutyryloxy, valeroyloxy, caproyloxy orpivaloyloxy.

Aliphatic, cycloaliphatic, aromatic and araliphatic radicals R₁ and R₂are, in particular, substituted or unsubstituted aliphatic,cycloaliphatic, aromatic or araliphatic hydrocarbon radicals, such ascorresponding lower alkyl, lower alkenyl, cycloalkyl, phenyl, naphthylor phenyl-lower alkyl. Substituents are, for example, hydroxyl, loweralkoxy, lower alkylthio or phenylthio, lower alkylsulphinyl orphenylsulphinyl or lower alkylsulphonyl or phenylsulphonyl, especiallyfor lower alkyl R₁ and lower alkyl R₂, and also lower alkyl, loweralkoxy and/or halogen, especially for phenyl or phenyl-lower alkyl R₁.Heterocyclyl in a heterocyclic or heterocyclic-aliphatic radical R₁ is,in particular, monocyclic heterocyclyl of aromatic character containinga hetero-atom, such as oxygen, sulphur or nitrogen, as a ring member,such as furyl, thienyl or pyridyl. In a heterocyclic-aliphatic radicalR₁, the aliphatic part is, for example, a corresponding aliphatichydrocarbon radical, especially lower alkyl.

Apart from being substituted by the radical of the formula R₁ --C(═O),1,2-phenylene can additionally be monosubstituted or polysubstituted,inter alia by lower alkyl, lower alkoxy, hydroxyl and/or halogen.

Lower alkoxy is, for example, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy, tert.-butoxy, n-pentyloxy or n-hexyloxy.

Phenyl-lower alkoxy is, for example, benzyloxy or 1-or 2-phenylethoxy.

Hydroxy-lower alkoxy, lower alkoxy-lower alkoxy and di-loweralkylamino-lower alkoxy are, especially, 2- and/or 3-hydroxy-loweralkoxy, for example 2-hydroxyethoxy, 3-hydroxypropoxy or2,3-dihydroxy-propoxy, and 2- or 3-lower alkoxy-lower alkoxy, forexample 2-methoxyethoxy, 2-ethoxyethoxy or 3-methoxypropoxy, and,respectively, di-lower alkylamino-lower alkoxy, for exampledimethylaminoethoxy or diethylaminoethoxy.

Lower alkyl is, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, tert.-butyl, n-pentyl, n-hexyl or n-heptyl.

Halogen is, especially, halogen with an atomic number of up to andincluding 35, i.e. fluorine, chlorine or bromine.

Lower alkylene is, for example, 1,4-butylene, 1,5-pentylene or1,6-hexylene.

Lower alkenyl is, for example, vinyl, 1-methyl-vinyl, 1-ethyl-vinyl,allyl, 2- or 3-methyl-allyl or 3,3-dimethylallyl.

Cycloalkyl preferably contains 3 to 8 ring atoms and is, for example,cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.

Lower alkylthio is, for example, methylthio or ethylthio, whilst loweralkylsulphinyl and lower alkylsulphonyl are, for example,methylsulphinyl, ethylsulphinyl, methylsulphonyl or ethylsulphonyl.

Lower alkyl substituted by lower alkylthio, lower alkylsulphinyl orlower alkylsulphonyl is, for example, methylthiomethyl orethylthiomethyl, 1- or 2-methylthioethyl or 1- or 2-ethylthioethyl or 2-or 3-methylthiopropyl or 2- or 3-ethylthiopropyl, methylsulphinylmethylor ethylsulphinylmethyl, 1- or 2-methylsulphinylethyl or 1- or2-ethylsulphinylethyl or 2- or 3-methylsulphinylpropyl or 2- or3-ethylsulphinylpropyl, or methylsulphonylmethyl orethylsulphonylmethyl, 1- or 2-methylsulphonylethyl or 1- or2-ethylsulphonylethyl or 2- or 3-methylsulphonylpropyl or 2- or3-ethylsulphonylpropyl. Lower alkyl substituted by phenylthio,phenylsulphinyl or phenylsulphonyl is, for example phenylthiomethyl,phenylsulphinylmethyl or phenylsulphonylmethyl, or 1- or2-phenylthioethyl, or 1- or 2-phenylsulphinylethyl or 1- or2-phenylsulphonylethyl.

Phenyl-lower alkyl is, for example, benzyl, 1- or 2-phenylethyl or 1-,2- or 3-phenylpropyl.

Furyl is, for example 2-furyl and thienyl is, for example 2-thienyl,whilst pyridyl can be 2-, 3- or 4-pyridyl.

Furyl-lower alkyl, thienyl-lower alkyl and pyridyl-lower alkyl are,especially, correspondingly substituted methyl radicals, such asfurfuryl, 2-thienyl or picolyl, for example 2- or 4-pyridylmethyl.

Salts are those of compounds of the formula I, in which R representscarboxyl, with bases; such salts are, especially, non-toxic salts, whichcan be used pharmaceutically, with bases, such as alkali metal salts oralkaline earth metal salts, for example sodium, potassium, magnesium orcalcium salts, and also ammonium salts with ammonia or amines, such aslower alkyl-amines or hydroxy-lower alkyl-amines, for exampletrimethylamine, triethylamine or di- or tri-(2-hydroxyethyl)-amine.

The novel compounds show valuable pharmacological properties. Inparticular, they show anti-allergic actions, which can be demonstrated,for example, on rats in doses of about 0.03 to about 10 mg/kg onintravenous administration and in doses of about 1 to about 100 mg/kg onoral administration in the passive cutaneous anaphylaxis test (PCAreaction), which is carried out analogously to the method described byGoose and Blair, Immunology, Volume 16, page 749 (1969), passivecutaneous anaphylaxis being produced by the procedure described byOvary, Progr. Allergy, Volume 5, page 459 (1958). The anti-allergicaction, and especially the degranulation-inhibiting action can bedetermined in an in vitro test, also with the aid of the release ofhystamine from peritoneal cells in rats, in the dosage range of about0.1 to about 100 μg/ml in the case of immunologically induced release(in which case, for example, rats infested with Nippostrongylusbrasiliensis are used) and of about 1.0 to about 100 μg/ml in the caseof chemically induced release (in which case, for example, this iseffected with a polymer of N-4-methoxy-phenylethyl-N-methyl-amine). Thecompounds of the present invention are accordingly useful as inhibitorsof allergic reactions, for example in the treatment and prophylaxis ofallergic diseases, such as asthma, including both extrinsic andintrinsic asthma, or other allergic diseases such as allergic rhinitis,for example hayfever or conjunctivitis or allergic dermatitis, forexample urticaria or eczema.

The invention relates especially to compounds of the formula I in whichR is free carboxyl or hydroxymethyl, esterified carboxyl or etherifiedhydroxymethyl containing, as the etherified hydroxyl group, loweralkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy or di-loweralkyl-amino-lower alkoxy, amidated carboxyl containing, as the aminogroup, amino, hydroxyamino, loweralkyl-amino, di-lower alkyl-amino orlower alkyleneamino, or esterified hydroxymethyl containing, as theesterified hydroxyl group, lower alkanoyloxy or benzyloxy which isunsubstituted or substituted by lower alkyl, lower alkoxy and/orhalogen, R₁ is lower alkyl, lower alkenyl or cycloalkyl, which areunsubstituted or substituted by lower alkoxy, lower alkylthio, loweralkylsulphinyl, lower alkylsulphonyl, phenylthio, phenylsulphinyl orphenylsulphonyl, or phenyl or phenyl-lower alkyl which are unsubstitutedor substituted in the phenyl part by lower alkyl, lower alkoxy orhalogen, or furyl, thienyl or pyridyl, or furyl-lower alkyl,thienyl-lower alkyl or pyridyl-lower alkyl, R₂ is hydrogen or loweralkyl and Ph is 1,2-phenylene which contains the radical of the formulaR₁ --C(═O)-- and is otherwise unsubstituted or substituted by loweralkyl, lower alkoxy, hydroxyl and/or halogen, with the proviso that R₁contains at least 2 carbon atoms if Ph is otherwise unsubstituted, R₂ isethyl and R is acetoxymethyl, and salts, especially salts which can beused pharmaceutically, of compounds of the formula I in which Rrepresents carboxyl.

The invention relates especially to compounds of the formula I in whichR is free carboxyl, esterified carboxyl containing, as the etherifiedhydroxyl group, lower alkoxy or hydroxy-lower alkoxy having up to andincluding 4 carbon atoms, for example methoxy, ethoxy, 2-hydroxyethoxyor 2,3-dihydroxypropoxy, or amidated carboxyl containing, as the aminogroup, amino or hydroxyamino or lower alkyl-amino or di-loweralkyl-amino in which lower alkyl contains up to and including 4 carbonatoms, for example methylamino, ethylamino, dimethylamino ordiethylamino, or hydroxymethyl, etherified hydroxymethyl containing, asthe etherified hydroxyl group, lower alkoxy having up to 4 carbon atoms,for example methoxy or ethoxy, or di-lower alkyl-amino-lower alkoxyhaving, in each case, up to 4 carbon atoms in the alkyl part and thealkoxy part, such as dimethylaminoethoxy, or esterified hydroxymethylcontaining, as the esterified hydroxyl group, lower alkanoyloxy havingup to 7 carbon atoms, for example acetoxy, propionyloxy or pivaloyloxy,or benzoyloxy which is unsubstituted or substituted by lower alkyl, forexample methyl, lower alkoxy, for example methoxy, and/or halogen, forexample chlorine, R₁ is lower alkyl having up to and including 7 carbonatoms, for example methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert.-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, loweralkoxy-lower alkyl, lower alkylthio-lower alkyl, loweralkylsulphinyl-lower alkyl or lower alkylsuphonyl-lower alkyl, in whichthe individual lower alkyl radicals contain up to and including 4 carbonatoms, for example methoxymethyl, ethoxymethyl, methylthiomethyl,ethylthiomethyl, methylsulphinylmethyl, ethylsulphinylmethyl,methylsulphonylmethyl or ethylsulphonylmethyl, 1- or 2-methoxyethyl, 1-or 2-ethoxyethyl, 1- or 2-methylthioethyl, 1- or 2-ethylthioethyl, 1- or2-methylsulphinylethyl, 1- or 2-ethylsulphinylethyl, 1- or2-methylsulphonylethyl or 1- or 2-ethylsulphonylethyl, or 1-, 2- or3-methoxypropyl, 1-, 2- or 3-ethoxypropyl, 1-, 2- or 3-methylthiopropyl,1-, 2- or 3-ethylthiopropyl, 1-, 2- or 3-methylsulphinylpropyl, 1-, 2-or 3-ethylsulphinylpropyl, 1-, 2- or 3-methylsulphonylpropyl or 1-, 2-or 3-ethylsulphonylpropyl, phenylthio-lower alkyl, phenylsulphinyl-loweralkyl or phenylsulphonyl-lower alkyl, in which the lower alkyl radicalcontains up to and including 4 carbon atoms, for examplephenylthiomethyl, phenylsulphinylmethyl or phenylsulphonylmethyl, 1- or2-phenylthioethyl, 1- or 2-phenylsulphinylethyl or 1- or2-phenylsulphonylethyl or 1-, 2- or 3-phenylthiopropyl, 1-, 2- or3-phenylsulphinylpropyl or 1-, 2- or 3-phenylsulphonylpropyl, loweralkenyl having up to and including 5 carbon atoms, for example 1-methyl-or 1-ethylvinyl, or allyl, cycloalkyl having up to and including 7carbon atoms, for example cyclopropyl or cyclohexyl, phenyl orphenyl-lower alkyl having up to and including 4 carbon atoms in thelower alkyl radical and being unsubstituted or substituted by loweralkyl having up to and including 4 carbon atoms, for example methyl,lower alkoxy having up to and including 4 carbon atoms, for examplemethoxy, and/or halogen having an atomic number of up to and including35, for example chlorine or bromine, for example benzyl or 1- or2-phenylethyl, or furyl, thienyl or pyridyl, for example 2-furyl,2-thienyl or 2-, 3- or 4-pyridyl, or furyl-lower alkyl, thienyl-loweralkyl or pyridyl-lower alkyl having up to and including 4 carbon atomsin the lower alkyl radical, for example furfuryl, 2-thienyl or 2- or4-picolyl, R₂ is hydrogen or lower alkyl having up to and including 4carbon atoms, for example methyl, and Ph is 1,2-phenylene which containsthe radical of the formula R₁ --C(═O)-- and is otherwise unsubstitutedor substituted by lower alkyl having up to and including 4 carbon atoms,for example methyl, lower alkoxy having up to and including 4 carbonatoms, for example methoxy, hydroxyl and/or halogen having an atomicnumber of up to and including 35, for example chlorine or bromine, theradical of the formula R₁ --C(═O)-- occupying any position suitable forsubstitution in the 1,2-phenylene radical, preferably the 4-position or5-position, with the proviso that R₁ contains at least 2 carbon atoms ifPh is otherwise unsubstituted, R₂ is ethyl and R is acetoxymethyl, andsalts, especially salts which can be used pharmaceutically, of suchcompounds of the formula I in which R is carboxyl, with bases.

The invention relates, in particular, to compounds of the formula##STR3## in which R' on the one hand is, in particular, carboxyl or alsoesterified carboxyl containing, as the etherified hydroxyl group, loweralkoxy having up to and including 4 carbon atoms, for example methoxy orethoxy, or amidated carboxyl containing, as the amino group, amino orhydroxyamino, or, on the other hand, in particular, hydroxymethyl oralso etherified hydroxymethyl containing, as the etherified hydroxylgroup, lower alkoxy having up to 4 carbon atoms, for example methoxy orethoxy, or di-lower alkyl-amino-lower alkoxy having up to 7 carbonatoms, for example dimethylaminoethoxy, or esterified hydroxymethylcontaining, as the esterified hydroxyl group, lower alkanoyloxy havingup to 7 carbon atoms, for example acetoxy, and in which R₁ ' is,especially, lower alkyl having up to and including 7 carbon atoms, forexample methyl, ethyl, n-propyl, n-butyl, tert.-butyl, n-pentyl, n-hexylor n-heptyl, and also lower alkoxy lower alkyl, lower alkylthio-loweralkyl, lower alkylsulphinyl-lower alkyl, phenylthio-lower alkyl orphenylsulphinyl-lower alkyl in which the lower alkyl radicals contain upto and including 4 carbon atoms, for example methoxymethyl,methylthiomethyl, methylsulphinylmethyl, phenylthiomethyl orphenylsulphinylmethyl, 2-methoxyethyl, 2-methylthioethyl,2-methylsulphinylethyl, 2-phenylthioethyl or 2-phenylsulphinylethyl or3-methoxypropyl, 3-methylthiopropyl, 3-methylsulphinylpropyl,3-phenylthiopropyl or 3-phenylsulphinylpropyl, cycloalkyl having up toand including 6 ring carbon atoms, for example cyclopropyl orcyclohexyl, or phenyl, furyl or pyridyl, for example 3- or 4-pyridyl, R₂' is, in particular, hydrogen and also lower alkyl having up to 4 carbonatoms, for example methyl and R₃ is hydrogen, lower alkyl having up toand including 4 carbon atoms, for example methyl, lower alkoxy having upto and including 4 carbon atoms, for example methoxy, hydroxyl orhalogen having an atomic number of up to and including 35, for examplechlorine, the radical of the formula R₁ '--C(═O)-- and the group R₃, ifthis differs from hydrogen, being able to occupy any position suitablefor substitution in the benzimidazole ring, preferably the 5-positionand the 6-position, with the proviso that R₁ ' contains at least 2carbon atoms if R₃ is hydrogen, R₂ ' is ethyl and R' is acetoxymethyl,and salts, especially salts which can be used pharmaceutically, of suchcompounds of the formula I in which R' represents carboxyl, with bases.

The invention relates, in particular, to the compounds of the formula Iain which R' is carboxyl or hydroxymethyl or also esterified carboxyl oretherified hydroxymethyl containing, as the etherified hydroxyl group,lower alkoxy having up to and including 4 carbon atoms, for examplemethoxy or ethoxy, and in which R₁ ' is lower alkyl having up to andincluding 7, and preferably having up to and including 4, carbon atoms,for example methyl, ethyl, n-propyl, isopropyl, n-butyl or tert.-butyl,cycloalkyl having up to and including 6 ring carbon atoms, for examplecyclopropyl or cyclohexyl, or phenyl, R₂ ' is, especially, hydrogen andis also lower alkyl having up to and including 4 carbon atoms, forexample methyl, and R₃ is hydrogen, lower alkyl having up to andincluding 4 carbon atoms, for example methyl, lower alkoxy having up toand including 4 carbon atoms, for example methoxy, or halogen having anatomic number of up to and including 35, for example chlorine, theradicals R₁ '--C(═O)-- and R₃, if this differs from hydrogen, preferablyoccupying the 5-position and 6-position respectively of thebenzimidazole ring, and salts, especially the salts which can be usedpharmaceutically, of such compounds of the formula Ia in which R'represents carboxyl, with bases.

The invention relates, in particular, to compounds of the formula Ia inwhich R' either is carboxyl or is hydroxymethyl and in which R₁ ' islower alkyl having up to and including 7 carbon atoms, for examplehaving up to and including 4 carbon atoms, for example methyl, ethyl,n-propyl, isopropyl or n-butyl, R₂ ' is hydrogen and R₃ is hydrogen orlower alkyl having up to and including 4 carbon atoms, for examplemethyl, the radical R₁ '--C(═O)-- occupying the 5-position of thebenzimidazole ring and a lower alkyl radical R₃ occupying the 6-positionof the benzimidazole ring, and salts, especially salts which can be usedpharmaceutically, of such compounds in which R' is carboxyl, with bases.

The invention relates specifically to the compounds of the formula Imentioned in the examples.

The novel compounds can be prepared in a manner which is known per se.Thus, for example, they can be obtained when a compound of the formulaII ##STR4## in which one of the radicals X₁ and X₂ is an optionallyetherified group of the formula --C(═O)--CH₂ OH and the other ishydrogen, or a salt thereof, is cyclised and, if desired, a compoundwhich is thus obtainable is converted into another compound of theformula I and/or a resulting free, salt-forming compound is convertedinto a salt or a resulting salt is converted into the free compound orinto another salt.

Salts of starting materials of the formula II which can be used are, forexample, acid addition salts, such as hydrohalides, for example thehydrochlorides, of compounds in which R is free, etherified oresterified hydroxymethyl and alkali metal salts or ammonium salts, forexample the sodium salts, of compounds in which R is carboxyl.

The cyclisation is effected in the customary manner at normaltemperature or, especially at elevated temperature, for example at about50° C. to about 160° C. and in particular at about 110° C. to 140° C.,if necessary in the presence of an acid condensing agent, such as ahydrogen halide acid, for example hydrochloric acid, and/or of awater-binding agent, for example dicyclohexylcarbodiimide, andadvantageously under an inert gas, for example under nitrogen.

The compounds resulting from the above process variant in which R isfree or etherified hydroxymethyl, can subsequently be converted easilyin the customary-manner into other compounds of the formula I.

The starting materials of the formula II are appropriately prepared insitu, for example by reacting a corresponding 1,2-phenylenediamine,which is substituted by the acyl radical of the formula R₁ --C(═O)--and, if desired, can contain yet further substituents, or an acidaddition salt thereof, for example the hydrochloride thereof, withglycollic acid, wherein the hydroxy group is free or etherified, or witha suitable reactive derivative thereof, preferably an ester, such as alower alkyl ester, an amide or an anhydride, such as the acid halide,thereof, especially with glycollic acid or a lower alkoxyacetic acid, ifnecessary in the presence of a solvent or diluent, such as a loweralkanol, for example methanol or ethanol, and/or with warming to about50° C. to about 160° C., for example to about 110° C. to about 140° C.The 1,2-phenylenediamines to be used as starting materials for thisprocess can be obtained, for example, by customary reduction of thecorresponding 1,2-nitroaniline compound, such as by reacting the saidcompound with a chemical reducing agent, such as sodium dithionite, orwith suitably activated hydrogen, such as hydrogen catalyticallyactivated by means of a noble metal catalyst in a basic medium, forexample by Raney nickel in methanol or ethanol. In a modification ofthis method, it is also possible to react this 1,2-nitroanilineintermediate with the abovementioned acid, especially with glycollicacid, or with a suitable derivative thereof, and subsequently to reducethe nitro group, for example with hydrogen in the presence of Raneynickel.

However, reduction of the nitro group can also be effected byintramolecular disproportionation, by subjecting a correspondingdisubstituted 1,2-nitroaniline of the formula R₁ --C(═O)--Ph(NO₂)--NR₂-ethyl to acid treatment, for example to the action of a Lewis acid,such as of zinc chloride in a carboxylic acid anhydride, for exampleacetic anhydride, cyclisation taking place to give the correspondingcompound of the formula I in which R is hydroxymethyl esterified by acarboxylic acid and R₂ differs from hydrogen.

When they are not known compounds, the 1,2-nitroaniline compounds to beused for the preparation of the starting materials of the formula II canbe prepared, for example, starting from the corresponding chlorobenzenesof the formula H--PhH--Cl by acylating these in the customary manner,for example by a reaction with a compound of the formula R₁ -COHal or(R₁ CO)₂ O in the presence of aluminium trichloride, nitrating thecompound of the formula R₁ --CO--PhH--Cl, which is thus obtainable, withnitric acid/sulphuric acid and reacting the chloronitro compound of theformula R₁ --CO-Ph(Cl)-No₂ which is thus obtainable, with ammonia or anamine of the formula R₂ NH₂.

The novel compounds can also be prepared by oxydising X₃ in a compoundof the formula ##STR5## in which X₃ is a formyl group or an optionallyetherified hydroxymethyl radical, R to an optionally esterified carboxygroup R and, if desired, converting a compound of the formula I, whichis thus obtainable, into another compound of the formula I and/or, ifdesired, converting a resulting salt into the free compound or intoanother salt and/or converting a free, salt-forming compound into asalt.

A group X₃ is, in particular the formyl group. This group can also beformed, for example from the methyl, aminomethyl or especiallyhydroxymethyl group or from a hydroxymethyl group esterified with aninorganic acid, such as a hydrogen halide acid, for example withhydrochloric acid, or hydroxymethyl group etherified with a cyclic2-hydroxy-ether, for example with 2-hydroxytetrahydropyrane, or a cyclic2- or 4-hydroxy-thioether, for example with 2-hydroxytetrahydrothiopyrane, 2-hydroxytetrahydrothiophene or4-hydroxy-4-methoxy-tetrahydrothiopyrane, or set free from one of itsderivatives such as a lower alkylene- or di-lower alkyl-acetal or animine for example benzylimine, in situ in the course of the oxidationreaction.

The oxidation can be carried out in a manner which is known per se, forexample by treatment with an oxidising heavy metal compound, preferablywith an oxidising compound containing chromium-VI or manganese-VII, forexample chromium trioxide or especially potassium permanganate, in thecase of starting materials of the formula II in which X₃ is the formylgroup or a radical which can be converted into the latter by oxidationmentioned, such as hydroxymethyl, and also with an oxidising compoundcontaining manganese IV, such as manganese dioxide, in the case ofstarting materials of the formula II in which X₃ is a etherifiedhydroxymethyl group. The reaction is advantageously carried out in thepresence of a suitable solvent or diluent, for example of acetone orpyridine or of a mixture, preferably an aqueous mixture, thereof, ifnecessary with cooling or warming, for example in a temperature range ofabout 0° C. to about 80° C.

The starting materials of the formula III can be prepared in a mannerwhich is known per se.

Compounds of the formula III in which X₃ is a formyl, can be prepared,for example, by reacting a corresponding compound of the formula##STR6## in which Y is a acetalised formyl group, such as loweralkylene-dioxymethyl or di-lower alkoxy-methyl, with a compound of theformula

    R.sub.1 --Y.sub.1                                          (IIIb),

wherein Y₁ is a group --M-Hal or --M/2, M is a metal atom of group II ofthe periodic table of the elements and Hal is chlorine, bromine oriodine, hydrolysing, for example by mild acid catalysis, a group of theformula --C(═NH)-R₁ which is first formed, and hydrolysing theacetalised formyl group, for example by acid catalysis.

Other starting materials of the formula III can be prepared startingfrom the corresponding 1,2-phenylenediamines, which are substituted bythe acyl radical of the formula --C(═O)-R₁ and can contain furthersubstituents and which are accessible from the correspondingnitroanilino compounds by reduction of the nitro group, for example byhydrogen in the presence of Raney nickel, in a manner analogous to thatdescribed for the treatment of these compounds with optionallyetherified glycollic acid or a suitable reactive derivative thereof, forexample by reaction with mono-lower alkoxy-acetic acid or a lower alkylester thereof.

Furthermore, starting materials of the formula III in which X₃represents formyl can also be obtained by reacting a benzimidazole whichis unsubstituted in the 1-position and 2-position, contains the acylgroup of the formula R₁ --C(═O)-- in the carbocyclic ring and cancontain further substituents, with 2-chloro-1,1,2-trifluoro-ethene andreacting the 1-(2-chloro-1,1,2-trifluoro-ethyl)-benzimidazole, which isthus obtainable and is unsubstituted in the 2-position, contains thegroup of the formula R₁ --C(═O)-- in the carbocyclic part and cancontain other substituents, with an alcohol, such as a lower alkanol,for example ethanol, in the presence of a base, such as an alkali metalhydroxide, for example sodium hydroxide, or with a hydroxylamine acidaddition salt, for example the hydrochloride, in the presence of a base,for example pyridine. This gives a compound of the formula III in whichX₃ is an acetalised formyl group, such as di-lower alkoxy-methyl, forexample diethoxymethyl, or is the hydroxyiminomethyl group, which groupscan be converted in a manner which is known per se, for example byhydrolysis, into the formyl group X₃.

The novel compounds in which R is a free, esterified or amidatedcarboxyl group or a free or etherified hydroxymethyl group can also beprepared by oxidising the group of the formula R₁ --CH(OH)-- in acorresponding compound of the formula ##STR7## or a salt thereof, to thedesired group of the formula R₁ --C(═O)-- and, if appropriate, oxidisinga free or esterified hydroxymethyl group to carboxyl and, if desired,converting a compound of the formula I, which is thus obtainable, intoanother compound of the formula I and/or, if desired, converting aresulting salt into the free compound or into another salt and/orconverting a free salt-forming compound into a salt.

The oxidation of the R₁ --CH(OH)-- group, which can also be formed insitu in the course of the oxidation reaction, for example from thecorresponding group of the formula R₁ --CH₂ --, or can be set free fromone of its derivatives, such as an ester, for example a hydrogen halideacid ester or lower alkan acid ester, is effected in the customarymanner. Oxidising agents which can be used are, for example, oxidisingheavy metal compounds, preferably oxidising compounds containingchromium-VI or managanese-VII. The reaction is advantageously carriedout in the presence of a suitable solvent or diluent, for example ofacetone or pyridine, or of a mixture thereof, preferably an aqueousmixture thereof, if necessary with cooling or warming, for example in atemperature range of from about 0° to about 80° C.

The compounds of the formula IV which are to be used a startingmaterials can be prepared, for example, by acylating correspondingchlorobenzene of the formula H--PhH--Cl in a manner which is known perse by reaction with a compound of the formula R₁ --COHal or (R₁ CO)₂ Oin the presence of aluminium trichloride, nitrating the compound of theformula R₁ --CO--PhH--Cl, which is thus obtainable, with nitricacid/sulphuric acid and reacting the chloronitro compound of the formulaR₁ --CO--Ph(Cl)--H which is thus obtainable, with ammonia or an amine ofthe formula R₂ NH₂ and reducing a corresponding compound of the formulaR₁ --C(═O)--Ph(NHR₂)--NO₂, which is thus obtainable, under mildconditions, for example with hydrogen in the presence ofpalladium-on-charcoal, advantageously in an inert solvent, such asdioxane, and under normal temperature and pressure conditions, andsubjecting the compound of the formula R₁ --CH(OH)--Ph(NHR₂)--NH₂, whichis thus obtainable, to a condensation reaction with an acid of theformula R--COOH or a suitable functional derivative thereof, for examplewith glycollic acid. The compounds of the formula ##STR8## which havebeen mentioned can also be prepared in an analogous manner by reducing,the nitroacyl intermediate of the formula R₁ --C(═O)--Ph(NHR₂)--NO₂ in acustomary manner, for example with zinc in acetic acid, to thecorresponding compound of the formula R₁ --CH₂ --Ph(NHR₂)--NH₂ andfurther reacting this compound in the indicated manner.

A compound of the formula I which is obtainable according to theinvention can be converted into another compound of the formula I in amanner which is known per se.

Thus, in a compound of the formula I in which R is carboxyl, this groupcan be converted into an esterified carboxyl group by esterificationprocesses which are known per se. Thus, for example, the esterificationcan be carried out by treatment with a suitable diazo compound, such a adiazo-lower alkane, with a suitable N,N-di-lower alkylformamide acetal,for example N,N-dimethylformamide diethyl acetal, orN,N-dimethylformamide methosulphate, or an oxonium salt, such as with atri-lower alkyl-oxonium tetrafluoborate or a tri-lower alkyloxoniumhexafluorophosphate, with a carbonate or pyrocarbonate, for example withdiethyl (pyro)carbonate, or with an organic sulphite or phosphite, suchas a di-lower alkyl sulphite or tri-lower alkyl phosphite, in thepresence of a suitable acid agent, such as p-toluenesulphonic acid, orwith an alcohol in the presence of a suitable condensing agent, such asa dehydrating agent, for example dicyclohexylcarbodiimide, or, in orderto form a hydroxy-lower alkyl group, with an epoxy-lower alkane, forexample ethylene oxide. Furthermore, it is possible to react a compoundof the formula I, in which a free carboxyl group R is in the form of asalt, for example in the form of an alkali metal salt, such as thesodium salt, with a reactive ester of an alcohol, for example with astrong acid, such as a corresponding halide, for example chloride,bromide or iodide, or disubstituted sulphate, or to react a compound ofthe formula I in which a free carboxyl group R is in the anhydride form,preferably in the form of a halogenocarbonyl group, for example achlorocarbonyl group, which can be formed, for example, by treating acompound of the formula I in which R represents carboxyl with ahalogenating agent, for example thionyl chloride, with a metalalcoholate or an alcohol in the presence of an acid-binding base andthus to obtain a compound of the formula I in which R is esterifiedcarboxyl. It is possible for any substituents which may be present in anesterifying reagent to be in the functionally modified form and then, ina compound of the formula I in which R, for example, is substitutedlower alkoxycarbonyl, in which substituents are in the functionallymodified form, for these substituents to be set free. Thus, for example,2,3-epoxy-propyl chloride can be used as the esterifying reagent and a2,3-epoxy-propoxy grouping R in the resulting ester can subsequently behydrolysed to the desired 2,3-dihydroxy-propoxy grouping.

In a compound of the formula I in which R is esterified carboxyl, forexample including p-nitro- or 2,4-dinitro-phenoxy-or-benzyloxy-carbonyl,this group can be converted by trans-esterification, for example bytreatment with an alcohol, if necessary in the presence of a suitabletrans-esterificationcatalyst, such as a substituted or unsubstitutedalkali metal alkanolate, for example a sodium alkanolate or potassiumalkanolate, into another esterified carboxyl group.

In a resulting compound of the formula I in which R is free carboxyl,carboxyl in the form of an anhydride or esterified carboxyl, this groupcan also be converted in a manner which is known per se into substitutedor unsubstituted carbamyl. Thus, a compound of the formula I in which acarboxyl group R is in the form of an anhydride, especially in the formof a halogenocarbonyl group, for example a chlorocarbonyl group, or inthe esterified form can be treated with ammonia, hydroxyamine or aprimary or secondary amine and compounds of the formula I in which R issubstituted or unsubstituted carbamyl can thus be obtained. Furthermore,the ammonium salt or an amine salt of a compound of the formula I inwhich R is carboxyl can be converted by dehydration with a suitabledehydrating agent, such as sulphuric acid, into a compound of theformula I in which R is substituted or unsubstituted carbamyl.

The compounds mentioned, in which R is carboxyl in the form of a halide,can be prepared starting from compounds of the formula I in which R iscarboxyl by treatment with a thionyl halide, such as thionyl chloride.If R₂ is hydrogen these compounds can dimerise to compounds of theformula ##STR9## An intermediate of this type can be converted into acompound of the formula I in which R is esterified carboxyl orsubstituted or unsubstituted carbamyl by, for example, treatment with asuitable alcoholate, such as an alkali metal alcoholate, for example asodium or potassium alcoholate, or with an alcohol in the presence of amineral acid, for example hydrogen chloride, or with ammonia,hydroxylamine or a primary or secondary amine.

An esterified carboxyl group or a substituted or unsubstituted carbamylgroup R in a compound of the formula I can be converted into the freecarboxyl group in a customary manner, for example by hydrolysis, usuallyin an alkaline medium, such as by treatment with water in the presenceof an alkali metal hydroxide or alkaline earth metal hydroxide, forexample sodium hydroxide.

In a compound of the formula I in which R₂ is hydrogen this can bereplaced by an aliphatic radical, for example by treatment with areactive ester of a corresponding alcohol, such as a halide, in thepresence of a base, for example of an alkali metal alcoholate.

A carboxyl group R, which can be free or in the form of a halide orsalt, can, furthermore, be reduced to hydroxymethyl by reaction with aborohydride or with hydrogen in the presence of a hydrogenationcatalyst. A borane, for example diborane or the borane-tetrahydrofuranecomplex, is preferably used for the reduction of a carboxyl group whichcan be in the form of a salt, for example in the form of an alkali metalsalt, such as the sodium salt. Halogenocarbonyl groups, such aschlorocarbonyl, are preferably reduced with hydrogen in the presence ofpalladium, preferably on a support, such as barium sulphate, and ifnecessary of a sulphur-containing co-catalyst, for example of thiourea.

Furthermore, in a compound of the formula I in which R representshydroxymethyl, this can be converted into an etherified hydroxymethylgroup in a customary manner, for example by reaction with an etherifyingagent. Etherifying agents are, for example, reactive esters ofcorresponding alcohols, for example esters thereof with an inorganicacid, such as hydrochloric acid, hydrobromic acid or hydriodic acid orsulphuric acid, or with organic sulphonic acids, for example withmethanesulphonic acid, benzenesulphonic acid, p-bromobenzenesulphonicacid or p-toluenesulphonic acid, and also epoxides derived fromcorresponding 1,2-diols. The reaction with the said etherifying agentscan be carried out in a customary manner, for example in the presence ofan alkali metal hydride or alkali metal alcoholate, for example ofsodium hydride or sodium methylate, or by employing the compound to beetherified in the form of a salt, for example the sodium salt.Furthermore, in a compound of the formula I in which R is hydroxymethyl,this can be esterified in a customary manner, for example converted intoan esterified hydroxymethyl group R by direct esterification with acorresponding carboxylic acid in the presence of a mineral acid, forexample of hydrochloric acid or sulphuric acid, or by reaction with areactive derivative, for example an anhydride, such as the anhydride orchloride, or an ester, such as a lower alkyl ester or p-nitrophenyl or2,4-dinitrophenyl ester, of the carboxylic acid, if necessary in thepresence of an acid or, in particular, basic condensing agent, forexample of pyridine in the case of the reaction with an acid anhydrideand, for example, of an alkali metal alcoholate, such as a sodium orpotassium alcoholate, in the case of the reaction with an ester.However, the etherification or esterification of a hydroxymethyl groupcan also be carried out by first converting this into a halogenomethylgroup in a customary manner, for example using phosphorus tribromide orthionyl chloride, and subsequently reacting this group with an alkalimetal alcoholate, for example the sodium alcoholate, of thecorresponding alcohol or an alkali metal salt, for example the sodiumsalt, of the corresponding carboxylic acid.

Free or esterified hydroxymethyl groups R can also be oxidised tocarboxyl groups and etherified hydroxymethyl groups can be oxidised toesterified carboxyl groups. The oxidation can be carried out in a mannerwhich is known per se, for example by reaction with an oxidising heavymetal compound, preferably with an oxidising compound containingchromium-VI or manganese-VII, for example with chromium trioxide or,especially, potassium permanganate, when starting from hydroxymethyl,and also with a compound containing manganese-IV, such as manganesedioxide, when starting from etherified hydroxymethyl R. The reaction ispreferably carried out in the presence of a suitable solvent or diluent,for example of acetone or pyridine, or of a mixture thereof, preferablyan aqueous mixture thereof, if necessary with cooling or warming, forexample in a temperature range of from about 0° C. to about 80° C.

Resulting free compounds of the formula I in which R is carboxyl can beconverted into salts in a manner which is known per se, inter alia bytreatment with a base or with a suitable salt of a carboxylic acid,usually in the presence of a solvent or diluent.

Resulting salts can be converted into the free compounds in a mannerwhich is known per se, for example by treatment with an acid reagent,such as a mineral acid.

The compounds, including their salts, can also be obtained in the formof their hydrates or can incorporate the solvent used forcrystallisation.

Because of the close relationship between the novel compounds in thefree form and in the form of their salts, the free compounds or theirsalts, in the preceding and following text, are, where appropriate, alsoto be understood as meaning the corresponding salts or free compounds inrespect of general sense and intended use.

The invention also relates to those embodiments of the process in whicha compound obtainable as an intermediate at any stage of the process isused as the starting material and the missing process steps are carriedout, or a starting material is formed under the reaction conditions oris used in the form of a derivative thereof, if appropriate in the formof a salt.

The starting materials used in the process of the present invention arepreferably those which lead to the compounds described initially asbeing particularly valuable.

The present invention also relates to pharmaceutical formulations whichcontain compounds of the formula I or salts thereof which can be usedpharmaceutically. The pharmaceutical formulations according to theinvention are those for enteral, such as oral, nasal or rectal, and alsoparenteral administration or topical application to warm-blooded animalsand contain the pharmacological active compound on its own or togetherwith an excipient which can be used pharmaceutically. The dosage of theactive compound depends on the species of warm-blooded animal, the ageand the state of health of the individual and also on the mode ofadministration.

The novel pharmaceutical formulations contain, for example, up to about95%, and preferably from about 5% to about 90%, of the active compound.Pharmaceutical formulations according to the invention are, for example,those in the form of dosage units, such as dragees, tablets, capsules orsuppositories, as well as ampoules and also inhalation formulations andalso pharmaceutical formulations which can be used topically and locally(for example for insufflation).

The pharmaceutical formulations of the present invention are prepared ina manner which is known per se, for example by means of conventionalmixing, granulating, dragee-making, dissolving or lyophilisingprocesses. Thus, pharmaceutical formulations for oral use can beobtained by combining the active compound with solid excipients,granulating a resulting mixture if desired and processing the mixture orgranules, after adding suitable auxiliaries if desired or necessary, togive tablets or dragee cores.

Suitable excipients are, especially, fillers, such as sugars, forexample lactose or sucrose, mannitol or sorbitol, cellulose formulationsand/or calcium phosphates, for example tricalcium phosphate or calciumhydrogen phosphate, as well as binders, such as starch paste using, forexample, maize starch, wheat starch, rice starch or potato starch,gelatine, tragacanth, methylcellulose and/or polyvinylpyrrolidone,and/or, if desired, disintegrating agents, such as the abovementionedstarches, and also carboxymethyl-starch, crosslinkedpolyvinylpyrrolidone, agar or alginic acid or a salt thereof, such assodium alginate. Auxiliaries are, in particular, flow control agents andlubricants, for example silica, talc, stearic acid or salts thereof,such as magnesium stearate or calcium stearate, and/or polyethyleneglycol. Dragee cores are provided with suitable coatings which, ifdesired, are resistant to gastric juices, and for this purpose, interalia, concentrated sugar solutions, which can contain gum arabic, talc,polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide,lacquer solutions in suitable organic solvents or solvent mixtures or,in order to produce coatings resistant to gastric juices, solutions ofsuitable cellulose formulations, such as acetylcellulose phthalate orhydroxypropylmethylcellulose phthalate, are used. Dyestuffs or pigmentscan be added to the tablets or dragee coatings, for example foridentification or in order to characterise different active compounddoses.

Other pharmaceutical formulations which can be used orally are push-fitcapsules made of gelatine, as well as soft, sealed capsules made ofgelatine and a plasticiser, such as glycerol or sorbitol. The push-fitcapsules can contain the active compound in the form of granules, forexample mixed with fillers, such as lactose, binders, such as starches,and/or lubricants, such as talc or magnesium stearate, and can containstabilisers. In soft capsules, the active compound is preferablydissolved or suspended in suitable liquids, such as fatty oils, liquidparaffin or liquid polyethylene glycols, it also being possible to addstabilisers.

Possible pharmaceutical formulations which can be used rectally are, forexample, suppositories, which consist of a combination of the activecompound with a suppository base. Suitable suppository bases are, forexample, natural or synthetic triglycerides, paraffin hydrocarbons,polyethylene glycols or higher alkanols. In addition it is also possibleto use gelatine rectal capsules which contain a combination of theactive compound with a base; bases which can be used are, for example,liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

Formulations suitable for parenteral administration are in particular,aqueous solutions of an active compound in the water-soluble form, forexample of a water-soluble salt, and also suspensions of the activecompound, such as corresponding oily injection suspensions, in whichcase suitable lipophilic solvents or vehicles, such as fatty oils, forexample sesame oil, or synthetic fatty acid esters, for example ethyloleate or triglycerides, are used, or aqueous injection suspensionswhich contain substances which increase the viscosity, for examplesodium carboxymethylcellulose, sorbitol and/or dextran and can alsocontain stabilisers.

Inhalation formulations for the treatment of the respiratory passages bynasal or buccal administration are, for example, aerosols or sprayswhich can disperse the pharmacological active compound in the form of apowder or in the form of drops of a solution or suspension. Formulationswhich have powder-dispersing properties usually contain, in addition tothe active compound, a liquid propellant gas which has a boiling pointbelow room temperature and also, if desired, excipients, such as liquidor solid non-ionic or anionic surface-active agents and/or soliddiluents. Formulations in which the pharmacological active compound isin solution contain, in addition to this active compound, a suitablepropellant and also, if necessary, and additional solvent and/or astabiliser. In place of the propellant gas, it is also possible to usecompressed air and this can be produced as required by means of asuitable compression and pressure release device.

Pharmaceutical formulations for topical and local use are, for example,lotions and creams which contain a liquid or semi-solid oil-in-water orwater-in-oil emulsion, and ointments (such formulations preferablycontaining a preservative) for the treatment of the skin, eye dropswhich contain the active compound in aqueous or oily solution and eyeointments, which are preferably prepared in a sterile form, for thetreatment of the eyes, powders, aerosols and sprays (similar to thosedescribed above for the treatment of the respiratory passages) and alsocoarse powders, which are administered through the nostrils by rapidinhalation, and nose drops, which contain the active compound in aqueousor oily solution, for the treatment of the nose or lozenges, whichcontain the active compound in a composition generally consisting ofsugar and gum arabic or tragacanth, to which flavourings can be added,as well as pastilles, which contain the active compound in an inertcomposition, for example consisting of gelatine and glycerol or sugarand gum arabic, for the local treatment of the mouth.

The invention also relates to the use of the novel compounds of theformula I, or salts thereof, as pharmacologically active compounds andespecially as anti-allergic agents, preferably in the form ofpharmaceutical formulations. The daily dose which is administered to awarm-blooded animal weighing about 70 kg is from about 2 mg of about7,000 mg, depending on the form of administration.

The examples which follow illustrate the invention described above;however, they are not intended to restrict the scope of the invention inany way. Temperatures are given in degrees Centigrade.

EXAMPLE 1

A mixture of 44.6 g of crude 4,5-diamino-2-methylbutyrophenone and 23 gof glycollic acid is heated, under a nitrogen atmosphere, to an internaltemperature of 130° and kept at this temperature for 21/2 hours. Thebrown-black reaction mass is cooled to room temperature and dissolved inabout 300 ml of 2 N hydrochloric acid; the brown solution, whichcontains flocculated material, is treated with an active charcoalformulation and filtered through a diatomaceous earth formulation(Hyflo). The pH of the clear brown filtrate is adjusted to 9 by addingan aqueous concentrated solution of sodium hydroxide. The mixture iscooled in an ice bath and the crystalline precipitate is filtered off,washed with water and dried under 100 mm Hg and at 50° for 6 hours. Theproduct is dissolved in 100 ml of hot ethanol, the solution is treatedwith an active charcoal formulation and filtered and the filtrate isdiluted with 100 ml of water.5-Butyryl-6-methyl-benzimidazole-2-methanol, which is thus obtainable,is filtered off and washed with water and di ether; melting point176°-178°.

The starting material can be obtained as follows:

A yellow suspension of 900 ml of 3-chloro-toluene and 367.5 g ofaluminium chloride (finely powdered) is treated with 266 g of butyrylchloride in the course of one hour. Hydrogen chloride gas evolves duringthe dropwise addition; the reaction is exothermic (the temperature isallowed to rise to 70°) and the aluminium chloride dissolves. After theaddition of the butyryl chloride is complete, the reaction mixture iskept at 70° until the evolution of gas has ceased (about 45 minutes) andis then cooled to 50° and poured onto 2,500 g of ice.

In each case, two identical batches are taken together and extractedwith ethyl acetate; the organic extract is washed twice with 2 Nhydrochloric acid, once with a saturated aqueous solution of sodiumchloride, twice with a 2 N aqueous solution of sodium carbonate and oncewith a saturated aqueous solution of sodium chloride, dried andevaporated. The brown, oily residue which is thus obtainable isdistilled; a mixture of 4-chloro-2-methyl-butyrophenone and2-chloro-4-methyl-butyrophenone is obtained at 160°-163°/14 mm Hg.

Concentrated sulphuric acid (1,275 ml), which has been cooled to -20° to-25° by means of a carbon dioxide/chloroform mixture, is treateddropwise, while stirring well, with 285.5 g of the mixture of4-chloro-2-methyl-butyrophenone and 2-chloro-4-methyl-butyrophenone inthe course of 10 minutes. The resulting solution is treated at -20° to-25° in the course of 30 minutes with a mixture of 240 ml ofconcentrated sulphuric acid and 75 ml of 100% strength nitric acid(d:1.52) and the mixture is then stirred for a further 15 minutes,during which time the temperature is allowed to rise to -15°. Themixture is poured into 8,000 ml of ice water; the oil which hasseparated out is extracted with chloroform. The organic extract iswashed once with an aqueous solution of sodium bicarbonate and once withwater, dried over sodium sulphate and evaorated. The residue isdissolved in twice the amount of hot methanol and the solution is leftto stand for 16 hours. The crystalline precipitate is filtered off,washed with cold water and dried under 100 mm Hg and at room temperaturefor 18 hours. This gives 4-chloro-2-methyl-5-nitro-butyrophenone whichmelts at 71°-72°.

A solution of 120.7 g of 4-chloro-2-methyl-5-nitrobutyrophenone in 250ml of dimethylsulphoxide is warmed to a temperature of 95°-100°, avigorous stream of ammonia already being passed through the solutionduring the heating period. The solution is treated with ammonia gas fora further 18 hours at a temperature of 95°-100° and is then cooled andpoured into about 5,000 ml of an ice/water mixture. The product startsto precipitate as a resin but crystallises on stirring. The mixture isfiltered; the coarse product is then ground and washed with water andthen dissolved in about 1,000 ml of ethyl acetate. The solution is driedover sodium sulphate and evaporated. The residue is dissolved in 245 mlof hot benzene and the solution is treated with an active charcoalformulation and filtered; the filtrate is diluted with 490 ml ofpetroleum ether and the crystalline4-amino-2-methyl-5-nitro-butyrophenone is filtered off; melting point90°-92°.

A solution of 66.6 g of 4-amino-2-methyl-5-nitro-butyrophenone in 600 mlof dioxane and 150 ml of water is heated under reflux, while stirring,and treated dropwise, in the course of 15 minutes, with a solution of240 g of sodium dithionite in 1,050 ml of water. The reaction mixture isboiled for a further 15 minutes and then treated dropwise, in the courseof 30 minutes, with 150 ml of concentrated hydrochloric acid; duringthis treatment a pH value of 3 is reached and a fairly large amount ofsulphur dioxide is formed. The organic solvent is evaporated; theresidue is rendered alkaline with an aqueous solution of sodiumhydroxide and extracted with chloroform. The organic extract is washedtwice with water, dried over sodium sulphate and evaporated.4,5-Diamino-2-methyl-butyrophenone of melting point 84°-87°, which isthus obtainable, is used without further purification.

EXAMPLE 2

The conversion of 4-chloro-2-methyl-5-nitro-butyrophenone into4,5-diamino-2-methyl-butyrophenone can, however, also be carried out inthe following way and in this case also a crude mixture of isomers canbe used as the starting material.

24.5 g of crude chloro-methyl-nitro-butyrophenone (containing about 75%of 4-chloro-2-methyl-5-nitro-butyrophenone) are dissolved in 300 ml ofethanol and the solution is transferred to an autoclave. 50 g of ammoniaare then injected and the mixture is heated at 100° for 12 hours. Themixture is evaporated to dryness under reduced pressure, the residue istreated with 200 ml of 2 N hydrochloric acid and the resulting mixtureis heated at 80°-90° for one hour, cooled to 10°-15° by adding ice andfiltered. The residue is dissolved in methylene chloride, dried oversodium sulphate and evaporated, with the addition of cyclohexane at theend. The crystalline 4-amino-2-methyl-5-nitro-butyrophenone is filteredoff and washed with petroleum ether. It melts at 92°-95°.

66.7 g of 4-amino-2-methyl-5-nitro-butyrophenone are dissolved in 900 mlof methanol, treated with 7 g of Raney nickel and hydrogenated at20°-25° under normal pressure. After 19.6 liters of hydrogen have beentaken up, the hydrogenation is discontinued, the catalyst is filteredoff, the filtrate is treated with 100 ml of concentrated hydrochloricacid and the methanol is stripped off under reduced pressure. The4,5-diamino-2-methyl-butyrophenone hydrochloride, which is nowcrystalline, is filtered off, washed with ethanol/ether and dried. Itmelts at above 160° with partial decomposition.

EXAMPLE 3

A suspension of 2.95 g of 5-butyryl-6-methyl-benzimidazol-2-yl-methanolin 180 ml of acetone is diluted with 140 ml of water and a solutionforms on stirring. This solution is treated, at room temperature, with2.95 g of potassium permanganate, which is added all at once, andstirred for a further one hour at room temperature, during which timethe violet coloration of the oxidising agent disappears and thebrown-black sludge of manganese dioxide separates out. The acetone isevaporated under reduced pressure and the resulting suspension isfiltered with the aid of a diatomaceous earth formulation (Hyflo) andthe material on the filter is washed with water. The pH of the filtrateis adjusted to 3 to 3.5 with acetic acid; the resulting flocculentprecipitate is filtered off, washed with water and dried at 35°.5-Butyryl-6-methyl-benzimidazole-2-carboxylic acid, which is thusobtainable, melts at 127°-137°, depending on the rate of heating andwith decomposition.

The sodium salt of 5-butyryl-6-methyl-benzimidazole-2-carboxylic acidcan be obtained by lyophilising a solution of the free acid in anaqueous solution of the equivalent amount of sodium hydroxide.

EXAMPLE 4

A mixture of 9.8 g of 5-amino-2-methyl-4-methylaminobutyrophenone and4.15 g of glycollic acid is heated in an oil bath at 130°. After 150minutes the reaction product, together with the product from a secondbatch of 3 g of 5-amino-2-methyl-4-methylamino-butyrophenone and 1.27 gof glycollic acid, is taken up in 300 ml of 2 N hydrochloric acid andthe mixture is filtered. The filtrate is rendered alkaline; the oilwhich has separated out is extracted with three portions of ethylacetate, the organic extract is washed twice with water, dried andfiltered and the filtrate is evaporated. The brown, oily residuecrystallises spontaneously and is recrystallised from ethyl acetate.5-Butyryl-1,6-dimethyl-benzimidazole-2-methanol, which is thusobtainable, melts at 141.5°-142.5°.

The starting material can be prepared as follows:

A mixture of 24.1 g of 4-chloro-2-methyl-5-nitrobutyrophenone and 250 mlof a 33% strength solution of methylamine in ethanol is left to stand atroom temperature; the crystalline starting material dissolves slowly anda yellow coloration develops. The reaction is slightly exothermic; themixture is therefore cooled using a water bath in order to prevent toomuch methylamine escaping. After 20 minutes everything has dissolved anda precipitate then starts to separate out. The mixture is left to standfor 16 hours at room temperature and is then evaporated to dryness underreduced pressure. The residue is treated with diethyl ether (about 1,000ml), ice and sodium carbonate, the mixture is shaken thoroughly and theorganic layer is separated off. This layer is washed twice with waterand the aqueous solution is back-washed with diethyl ether. The combinedorganic solutions are dried over sodium sulphate and filtered and thefiltrate is evaporated to a volume of about 300 ml, then diluted with100 ml of petroleum ether and cooled. Yellow, crystalline2-methyl-4-methylamino-5-nitro-butyrophenone precipitates and isfiltered off, washed with petroleum ether and dried in air; meltingpoint 107°-108°.

A solution of 4.7 g of 2-methyl-4-methylamino-4-nitrobutyrophenone in 40ml of dioxane is diluted with water and heated to the reflux temperatureand then treated, in the course of 10 minutes, with a solution of 16 gof sodium dithionite in 70 ml of water, whereupon the yellow colour ofthe reaction mixture pales. The mixture is boiled under reflux for afurther 15 minutes, the pH value is adjusted to 3 by adding about 30 mlof 6 N hydrochloric acid and the mixture is boiled for a further 15minutes under reflux, during which time the sulphur dioxide escapes. ThepH value of the reaction mixture is adjusted to 2, the mixture is boiledunder reflux for about a further 5 minutes and the dioxane is thenevaporated under reduced pressure. The hydrochloride of5-amino-2-methyl-4-methylamino-butyrophenone precipitates from theresidual solution; the suspension is cooled, rendered alkaline with aconcentrated aqueous solution of sodium hydroxide and extracted withchloroform. The organic extract is washed twice with water, dried,filtered and evaporated. 5-Amino-2-methyl-4-methylamino-butyrophenonemelts at 126°-128°.

EXAMPLE 5

The conversion of 4-chloro-2-methyl-5-nitro-butyrophenone into4-amino-2-methyl-5-methylamino-butyrophenone can also be carried out inthe following way and a crude mixture of isomers can also be used as thestarting material.

241 g of crude chloro-methyl-nitrobutyrophenone (containing about 75% of4-chloro-2-methyl-5-nitro-butyrophenone) are suspended in 1,200 ml ofethanol and the suspension is treated with 1,200 ml of 33% strengthmethylamine solution, whereupon a solution forms, an exothermic reactiontaking place. The solution is left to stand for 2 days and is evaporatedto dryness under reduced pressure, the residue is treated with 600 ml of2 N hydrochloric acid and the mixture is warmed at 80°-90° for 1 hour.It is cooled to about 15° by adding ice and the crystalline precipitateis filtered off, washed with water and taken up in methylene chloride,the solution is dried over sodium sulphate and the methylene chloride isevaporated under reduced pressure, finally with the addition ofcyclohexane and petroleum ether (boiling range 60°-80°), the residue iscooled and 2-methyl-4-methylamino-5-nitrobutyrophenone with a meltingpoint of 105°-107° is filtered off.

59.1 g of 2-methyl-4-methylamino-5-nitro-butyrophenone are dissolved in1,000 ml of methanol, treated with 6 g of Raney nickel and hydrogenatedat 20°-25° under normal pressure. After 16.8 liters of hydrogen havebeen taken up, the hydrogenation is discontinued, the mixture is warmedgently to dissolve the material which has precipitated, the catalyst isfiltered off and the filtrate is treated with 50 ml of concentratedhydrochloric acid, cooled to 3° and filtered. This gives4-amino-2-methyl-5-methylamino-butyrophenone hydrochloride with amelting point above 180° (decomposition).

EXAMPLE 6

A solution of 1.23 g of 5-butyryl-1,6-dimethyl-benzimidazole-2-methanolin 75 ml of acetone and 25 ml of water is treated, while stirring, with1.2 g of potassium permanganate, which is added all at once. After aninitially weakly exothermic reaction, manganese dioxide begins toprecipitate after 30 minutes. After four hours the reaction mixture istreated with a small amount of isopropanol and the organic solvent isthen evaporated under reduced pressure. The residual aqueous suspensionis filtered through a diatomaceous earth formulation (Hyflo). The turbidfiltrate is extracted twice with chloroform and the organic extract isdiscarded. The aqueous phase is freed from the final traces ofchloroform under reduced pressure and then treated with an activecharcoal formulation and filtered. The pH of the filtrate is adjusted to3-4 with acetic acid and5-butyryl-1,6-dimethylbenzimidazole-2-carboxylic acid then starts toprecipitate in the form of fine needles. The mixture is cooled and theprecipitate is filtered off, washed with water and diethyl ether anddried at room temperature under a high vacuum; melting point above 110°(decomposition). The sodium salt melts at 275°-280° (from aqueousacetone).

EXAMPLE 7

A mixture of 2.9 g of 3,4-diamino-valerophenone and 1.5 g of glycollicacid is heated at 130° for 2 hours under a nitrogen atmosphere. Aftercooling, the reaction product is taken up in 2 N hydrochloric acid; thesolution is treated with an active charcoal formulation and filteredthrough a diatomaceous earth formulation (Hyflo) and the filtrate isrendered alkaline by adding a concentrated aqueous solution of sodiumhydroxide. The crystalline precipitate is filtered off, washed withwater and diethyl ether and dried.5(6)-Valeryl-benzimidazole-2-methanol, which is thus obtainable, meltsat 134°-136°.

The starting material can be prepared as follows:

A mixture of 346 ml of chlorobenzene and 120 g of valeryl chloride istreated, at room temperature, in the course of 1 hour with portions ofaluminium chloride and the mixture is at the same time heated to 70°.The mixture is stirred for a further hour at this temperature and thencooled to 25° and the dark red reaction mixture is poured on to 1,000 gof ice. Concentrated hydrochloric acid is added and the mixture is thenextracted with ethyl acetate. The organic extract is washed with 2 Nhydrochloric acid, filtered through a diatomaceous earth formulation(Hyflo) and washed with further 2 N hydrochloric acid, twice with water,with a 2 N aqueous solution of sodium carbonate and with water. It isdried over sodium sulphate and filtered and the filtrate is evaporatedunder reduced pressure. The residue is distilled; 4-chlorovalerophenoneis obtained at 155°-156°/14 mm Hg; the product crystallises and melts at28°-30°.

50 ml of concentrated sulphuric acid are treated, while stirring, with9.9 g of 4-chloro-valerophenone, while cooling with an ice/sodiumchloride mixture. The bulk of the product dissolves, a slightlyexothermic reaction taking place, and a yellow suspension forms, whichis treated, while stirring vigorously and at a temperature of -10° to-5°, with a mixture of 20 ml of concentrated sulphuric acid and 10.4 mlof concentrated nitric acid (d=1.52), in the course of 10 minutes. Aftera reaction time of five minutes, the mixture is poured onto ice and theaqueous mixture is extracted with chloroform. The organic extract iswashed once with an aqueous solution of sodium carbonate and with water,dried over sodium sulphate and filtered through silica gel.4-Chloro-3-nitro-valerophenone is obtained as an oily residue afterevaporating the filtrate.

Gaseous ammonia is passed through a solution of 18.1 g of4-chloro-3-nitro-valerophenone in 40 ml of dimethylsulphoxide at roomtemperature. A yellow coloration develops immediately and the solutionwarms to above 40°. After 105 minutes (final temperature: 32°), thereaction mixture is heated, while continuing to pass in ammonia, to 70°,kept at this temperature for two hours and then heated at 95° for afurther two hours. After cooling, the mixture is poured into about 400ml of water and the resulting mixture is then acidified withconcentrated hydrochloric acid and, after a few minutes, renderedalkaline again using concentrated aqueous ammonia solution. The yellowcrystalline precipitate is filtered off; the moist crystals are taken upin ethyl acetate, the solution is dried over sodium sulphate andfiltered and the filtrate is evaporated. The crystalline residue isdissolved in hot benzene and the solution is treated with silica gel andfiltered. The filtrate, which is still brown, is diluted with petroleumether and the hot mixture is again treated with silica gel and filtered.The filtrate is diluted with petroleum ether;4-amino-3-nitro-valerophenone crystallises out and is filtered off;melting point 115°-117°.

A suspension of 3.9 g of 4-amino-3-nitro-valerophenone in 35 ml ofdioxane and 9 ml of water is heated to the reflux temperature and theresulting solution is treated, in the course of 10 minutes, whileboiling, with 14 g of sodium dithionite in 60 ml of water. The reactionmixture is boiled under reflux for a further 15 minutes and 6 Nhydrochloric acid is then added dropwise until the pH is 3, a littlesulphur dioxide escaping. The pH value is adjusted to 2, the mixture isallowed to react for a few minutes and the organic solvent is thenremoved under reduced pressure. The residual aqueous suspension isrendered alkaline in the cold and extracted with 5 50 ml portions ofchloroform. The combined organic extracts are washed twice with water,dried and filtered and the filtrate is evaporated.3,4-Diamino-valerophenone is obtained in the form of brown crystals;melting point 106°-107°.

EXAMPLE 8

A solution of 1.15 g of 5(6)-valeryl-benzimidazole-2-methanol in 75 mlof acetone and 55 ml of water is heated with 1.15 g of potassiumpermanganate, which is added all at once, and the mixture is stirred atroom temperature for one hour. After 5 minutes managanese dioxide beginsto precipitate and after 30 minutes the violet colour has disappeared.The acetone is evaporated under reduced pressure; the residual mixtureis filtered through a diatomaceous earth formulation (Hyflo) and thefilter residue is washed with water. The filtrate is acidified to pH 4with acetic acid; the resulting precipitate is filtered off, washed withwater and dried at room temperature.5(6)-Valeryl-benzimidazole-2-carboxylic acid, which is thus obtainable,melts at 145° (with decomposition).

EXAMPLE 9

It is possible to prepare the following compounds inter alia, in amanner analogous to that described in Examples 1, 2, 4, 5, 7 and 8.

5-Acetyl-6-methyl-benzimidazole-2-carboxylic acid;6-methyl-5-propionyl-benzimidazole-2-carboxylic acid;6-methyl-5-valeryl-benzimidazole-2-carboxylic acid;5(6)-butyrylbenzimidazole-2-carboxylic acid;5-butyryl-6-methoxy-benzimidazole-2-carboxylic acid;5-butyryl-6-chloro-benzimidazole-2-carboxylic acid;5-cyclopropylcarbonyl-6-methyl-benzimidazole-2-carboxylic acid;5-cyclohexylcarbonyl-6-methyl-benzimidazole-2-carboxylic acid;5-(4-methoxy-butyryl)-6-methyl-benzimidazole-2-carboxylic acid;6-methyl-5-(4-methylthiobutyryl)-benzimidazole-2-carboxylic acid;6-methyl-5-(4-methylsulphinyl-butyryl)-benzimidazole-2-carboxylic acid;6-methyl-5-(4-phenylthio-butyryl)-benzimidazole-2-carboxylic acid;6-methyl-5-(4-phenylsulphinyl-butyryl)-benzimidazole-2-carboxylic acid;and methyl 5-butyryl-6-methyl-benzimidazole-2-carboxylate.

EXAMPLE 10

59.1 g of 2-methyl-4-methylamino-5-nitro-butyrophenone are dissolved in1,000 ml of methanol, treated with 6 g of Raney nickel and hydrogenatedat 20°-25° under normal pressure. After 17.2 liters of hydrogen havebeen taken up, the hydrogenation is discontinued and the reactionmixture is warmed gently and treated, under nitrogen, with a solution of17.1 g of glycollic acid in 30 ml of methanol. The catalyst is filteredoff, the filtrate is evaporated to dryness under reduced pressure andthe residue is heated at 130° for 3 hours. After cooling, the residue isdissolved in 2 N hydrochloric acid and the solution is washed with ethylacetate, rendered alkaline and extracted with methylene chloride. Theextract is washed twice with water, concentrated to 100 ml and treatedwith ethyl acetate and all of the methylene chloride is stripped off.5-Butyryl-1,6-dimethyl-benzimidazole-2-methanol with a melting point of141.5°-142.5°, which has precipitated, is filtered off and dried invacuo.

The starting material can be prepared as follows:

241 g of chloro-methyl-nitro-butyrophenone (containing about 75% of4-chloro-2-methyl-5-butyrophenone) are suspended in 1,200 ml of ethanoland the suspension is treated with 1,200 ml of 33% strength methylaminesolution and warmed gently. When the exothermic reaction starts, themixture is cooled somewhat and then left to stand at room temperaturefor 2 days. It is evaporated to dryness under reduced pressure, theresidue is treated with 600 ml of 2 N hydrochloric acid, the mixture isheated to 80°-90° for 1 hour and cooled to about 15° by adding ice andthe precipitate is filtered off. It is washed with water and dissolvedin methylene chloride, the solution is dried over sodium sulphate andconcentrated under reduced pressure and cyclohexane is added, all of themethylene chloride is stripped off and the product is filtered off anddried in vacuo. 2-Methyl-4-methylamino-5-nitrobutyrophenone melts at105°-107°.

EXAMPLE 11

41.5 g of 4-amino-2-methyl-5-nitro-valerophenone dissolved in 500 ml ofmethanol are treated with 4 g of Raney nickel and hydrogenated undernormal pressure until 11.6 liters of hydrogen have been taken up. Thecrude hydrogenation solution, which contains the3-methyl-4-valeryl-1,2-phenylenediamine formed, is treated, undernitrogen, with a solution of 26.6 g of glycollic acid in 100 ml ofmethanol and the catalyst is filtered off. The methanol is stripped offunder reduced pressure and the residue is heated at 130° for 90 minutesand after cooling is treated with 400 ml of 2 N hydrochloric acid andthe mixture is stirred for one hour, treated with a filter aid andfiltered through diatomaceous earth. The filtrate is brought to pH 9,first with concentrated sodium hydroxide solution and then with 4 Nsodium carbonate solution, and cooled, whereupon6-methyl-5-valeryl-benzimidazole-2-methanol precipitates out. This isfiltered off with suction, washed with 200 ml of ethyl acetate and driedunder reduced pressure. The product melts at 169°-171°. A furtherproduct with a melting point of 168°-170° can be obtained from the ethylacetate used for washing, by concentrating to about 50 ml.

The starting material can be prepared as follows:

302 g of valeroyl chloride are added dropwise, in the course of 120minutes, to a stirred suspension of 367 g of aluminium trichloride in900 ml of m-chlorotoluene. The reaction temperature should not exceed45°; if necessary, the reaction mixture is cooled with ice water. Themixture is stirred for several hours more, poured onto 4,000 g of iceand extracted with ethyl acetate. The combined extracts are washedsuccessively with 2 N hydrochloric acid, water, 2 N sodium carbonatesolution and twice with water, dried over sodium sulphate and evaporatedunder reduced pressure, finally at 80°. The residue is distilled underreduced pressure and a mixture of isomers containing about 50% of4-chloro-2-methyl-valerophenone passes over at 150° and under 12 mm Hg.

130 ml of sulphuric acid cooled to -23° are treated dropwise, at -25° to-20°, first with the mixture of isomers containing about 50% of4-chloro-2-methyl-valerophenone and then with a mixture of 24 ml ofsulphuric acid and 7.5 ml of nitric acid with a density of 1.52. Thereaction has ended after about 20 minutes. The mixture is poured on to600 g of ice, the precipitate is filtered off with suction and taken upin chloroform and the solution is washed successively with a saturatedsolution of sodium carbonate and twice with water, dried over sodiumsulphate and evaporated to dryness. The evaportion residue is taken upin 40 ml of methanol. A mixture of isomers containing about 50% of4-chloro-2-methyl-5-nitro-valerophenone crystallises out on cooling.This mixture is filtered off and washed with cold methanol.

Ammonia is passed into a solution, which has been heated to 95°-100°, of38 g of the mixture of isomers containing about 50% of4-chloro-2-methyl-5-nitro-valerophenone, in 20 ml of dimethylsulphoxide,for about 14 hours until an intense yellow coloration has developed. Themixture is allowed to cool and is poured onto 2,000 g of ice, theresulting mixture is acidified with concentrated hydrochloric acid andrendered alkaline with sodium hydroxide solution and the precipitate isfiltered off with suction, washed with water, dried at 40°, suspended inboiling cyclohexane and again filtered off with suction. This gives4-amino-2-methyl-5-nitro-valerophenone with a melting point of108°-112°, which is pure according to chromatography.

EXAMPLE 12

A solution of 9.85 g of 6-methyl-5-valeryl-benzimidazole-2-methanol in amixture of 350 ml of acetone and 80 ml of water is treated with 9.5 g ofpotassium permanganate, while stirring at room temperature. Theexothermic reaction, which starts immediately, can be controlled, ifnecessary, by external cooling with ice water. After 2 hours the mixtureis filtered through diatomaceous earth, the acetone is stripped off fromthe filtrate under reduced pressure and the solution is filtered, ifnecessary with the aid of a filter aid, to give a clear filtrate. Thefiltrate is acidified with acetic acid and the fine precipitate whichseparates out is filtered off with suction and dissolved in 100 ml of Nsodium hydroxide solution, and pH is brought back to 7.5 and thesolution is again filtered to give a clear filtrate. The filtrate isacidified and 6-methyl-5-valeryl-benzimidazole-2-carboxylic acid, whichprecipitates immediately, is filtered off with suction, washed withwater and dried in vacuo. The product starts to melt at 132°, withdecomposition.

EXAMPLE 13

A solution of 30.1 g of 4-amino-3-nitro-bytyrophenone in 300 ml ofmethanol is treated with 3 g of Raney nickel and hydrogenated at 20°-35°under normal pressure. After 9.87 liters of hydrogen have been taken up,a solution of 21.9 g of glycollic acid in 50 ml of methanol is addedunder nitrogen, the catalyst is filtered off and the filtrate isevaporated to dryness. The evaporation residue is heated to 130° for 90minutes and after cooling is dissolved in 600 ml of 2 N hydrochloricacid, the solution is filtered, the pH of the filtrate is adjuted to 8and the resulting mixture is extracted with a total of about 2,000 ml ofmethylene chloride. The combined extracts are concentrated to about 200ml under reduced pressure. The precipitate is filtered off, suspended in200 ml of ethyl acetate, filtered off again and dried in vacuo. Thisgives 5(6)-butyryl-benzimidazole-2-methanol with a melting point of141°-143°.

The starting material can be prepared as follows:

A solution of 18.3 g of 4-chloro-butyrophenone in 100 ml of sulphuricacid at -20° is treated, in the course of 5 minutes, at -20° to -15°,with a mixture of 40 ml of sulphuric acid and 21 ml of fuming nitricacid, whereupon everything dissolves. The solution is stirred for afurther 45 minutes at -15° to -10° and poured onto 1,000 g of ice, theprecipitate is filtered off, washed with water and taken up inchloroform, the chloroform solution is washed with a saturated solutionof sodium bicarbonate and twice with water, dried over sodium sulphateand filtered and the filtrate is evaporated to dryness. The evaporationresidue is digested with 25 ml of methanol. This gives4-chloro-3-nitro-butyrophenone with a melting point of 52°-54°.

50 g of ammonia are injected into a solution of 22.8 g of4-chloro-3-nitro-butyrophenone in 300 ml of ethanol in an autoclave. Themixture is warmed to 100° for 10 hours and after cooling to roomtemperature is evaporated to dryness under reduced pressure, the residueis warmed with 200 ml of 2 N hydrochloric acid to 80°-90° for 1 hour,the mixture is cooled to 15° by adding ice and filtered and the materialon the filter is washed with water. The material on the suction filteris taken up in 1,000 ml of methylene chloride, the solution is driedover sodium sulphate, concentrated and treated with petroleum ether(boiling range 60°-80°) and all of the methylene chloride is evaporated.4-Amino-3-nitro-butyrophenone, which has precipitated as crystals, isfiltered off and dried in vacuo. It melts at 128°-129°.

EXAMPLE 14

A solution of 6.5 g of 5(6)-butyryl-benzimidazole-2-methanol in 300 mlof acetone and 60 ml of water is treated with 0.5 g of potassiumpermanganate and the mixture is cooled briefly in a water bath andstirred at room temperature for 3 hours. It is then filtered throughdiatomaceous earth, the acetone is stripped off under reduced pressure,the residue is extracted twice with chloroform, the chloroform solutionis filtered through diatomaceous earth, if necessary using a filter aid,and the filtrate is acidified with 2 N acetic acid.5(6)-Butyryl-benzimidazole-2-carboxylic acid, which has precipitated, isfiltered off, washed with water and dried in vacuo. It melts at above150°.

EXAMPLE 15

A solution of 35.5 g of 4-methylamino-3-nitro-acetophenone in 500 ml ofmethanol is treated with 4 g of Raney nickel and hydrogenated at30°-35°. After 12.7 liters of hydrogen have been taken up, the mixtureis treated, under nitrogen, with a solution of 27.3 g of glycollic acidin 100 ml of methanol, the catalyst is filtered off and the filtrate isevaporated to dryness under reduced pressure. The residue is heated to130° for 90 minutes, under nitrogen. After cooling to room temperature,it is dissolved in 300 ml of 2 N hydrochloric acid and the solution isfiltered, if necessary using a filter aid. The pH of the filtrate isbrought to 7-8 with concentrated sodium hydroxide solution and finallywith sodium carbonate solution and the mixture is extracted by shakingwith methylene chloride. The methylene chloride phase is separated offand washed with water. The aqueous phase is extracted 5 times by shakingwith methylene chloride. The combined methylene chloride phases areconcentrated to 300 ml and the5-acetyl-1-methyl-benzimidazole-2-methanol with a melting point of178°-179°, which has precipitated, is filtered off. Further product witha melting point of 176°-177° can be obtained by concentrating the motherliquor to 100 ml.

The starting material can be prepared as follows:

A solution of 15.5 g of 4-chloroacetophenone in 100 ml of sulphuric acidat -20° is treated, in the course of 2 minutes, with a mixture of 40 mlof sulphuric acid and 21 ml of fuming nitric acid, the mixture isstirred for 1 hour at -25° to -20° and poured onto 600 g of ice and theprecipitate is filtered off, washed with water and taken up inchloroform. The chloroform solution is washed with a saturated solutionof sodium bicarbonate and twice with water, dried over sodium sulphateand filtered and the filtrate is evaporated to dryness. The evaporationresidue is recrystallized from 50 ml of methanol. This gives4-chloro-3-nitro-acetophenone with a melting point of 92°-95°.

39.9 g of 4-chloro-3-nitro-acetophenone are suspended in 200 ml ofethanol and the suspension is treated with 200 ml of a 33% strengthaqueous solution of methylamine, stirred until crystallization startsand then left to stand for several days, shaking occasionally. Themixture is evaporated to dryness under reduced pessure, 200 ml of 2 Nhydrochloric acid are poured over the residue and the resulting mixtureis warmed to 30°, allowed to cool, rendered alkaline and extracted withmethylene chloride. The extract is washed with water, dried over sodiumsulphate and filtered and the filtrate is evaporate.4-Methylamino-3-nitro-acetophenone, which remains behind, isrecrystallized from cyclohexane. It melts at 118°-120°.

EXAMPLE 16

In a manner analogous to that described in Example 12, 4.1 g of5-acetyl-1-methyl-benzimidazole-2-methanol can be oxidised with 4 g ofpotassium permanganate to give5-acetyl-1-methyl-benzimidazole-2-carboxylic acid with a melting pointabove 135°.

EXAMPLE 17

In a manner analogous to that described in Example 15,5-butyryl-1-methyl-benzimidazole-2-methanol with a melting point of153°-154° is obtained starting from 34.2 g of4-chloro-3-nitro-butyrophenone, 100 ml of a 33% strength aqueoussolution of methylamine and 20 g of glycollic acid, via4-methylamine-3-nitro-butyrophenone with a melting point of 71°.

EXAMPLE 18

In a manner analogous to that described in Example 12, 18.5 g of5-butyryl-1-methyl-benzimidazole-2-methanol can be oxidised with 18.5 gof potassium permanganate to give5-butyryl-1-methyl-benzimidazole-2-carboxylic acid with a melting pointabove 90° (decomposition).

EXAMPLE 19

A solution of 18.8 g of 2-chloro-4-methylamino-5-nitrobutyrophenone in190 ml of methanol is treated with 2 g of Raney nickel and hydrogenatedat 20°-27° under normal pressure. After 5 liters of hydrogen have beentaken up, a solution of 11.4 g of glycollic acid in 50 ml of methanol isadded under nitrogen, the catalyst is filtered off and the filtrate isevaporated to dryness under reduced pressure. The residue is warmed to130° to 1 hour, under nitrogen, and after cooling is ground withmethanol, whereupon crystallisation starts. The crystalline product iscooled, filtered off and washed with cold methanol. This gives5-butyryl-6-chloro-1-methyl-benzimidazole-2-methanol with a melting pontof 183°-185°.

The starting material can be prepared as follows:

293 g of aluminium trichloride are added to 685 ml of m-dichlorobenzene,the mixture is warmed to 70° and 213 g of butyrl chloride are addeddropwise, while stirring, at 70°-90° in the course of 30 minutes. Themixture is stirred for a further 2 hours at 80°-90° and after cooling ispoured onto 3,000 g of ice and extracted with ethyl acetate. Theextracts are washed successively with 2 N hydrochloric acid, water, 2 Nsodium carbonate solution and twice with water, dried over sodiumsulphate and highly concentrated, finally at 70° under a water pumpvacuum. The residue is distilled. 2,4-Dichlorobutyrophenone has aboiling point at 12 mm Hg of 135°-141°.

A mixture of 24 ml of sulphuric acid and 7.5 ml of fuming nitric acid isadded, in the course of 10 minutes, at -25° to -20°, to a solution,which has been cooled to -23°, of 32.6 g of 2,4-dichlorobutyrophenone in130 ml of sulphuric acid and the resulting mixture is stirred for afurther 15 minutes at -25° to -20°, poured onto ice and extracted withchloroform. The extracts are washed successively with water, sodiumbicarbonate solution and twice with water, dried over sodium sulphateand evaporated. 2,4-Dichloro-5-nitro-butyrophenone with a melting pointof 145°-50° can be further reacted as the crude product by dissolving26.2 g of this product in 50 ml of ethanol and adding this solutiondropwise to 150 ml of a 33% strength aqueous solution, which has beencooled to 8°, of methylamine. The mixture is stirred for a further 2hours at 5° to 8° and evaporated to dryness under reduced pressure, theresidue is treated with 150 ml of 2 N hydrochloric acid and theresulting mixture is warmed to 80°-90° for a few minutes. It is thencooled with ice to 10°, the precipitate is filtered off, washed withwater and dissolved in methylene chloride, the resulting solution isdried over sodium sulphate, concentrated under reduced pressure, treatedwith cyclohexane and cooled to 15° and2-chloro-4-methylamino-5-nitro-butyrophenone is filtered off. Afterdrying it melts at 95°-97°.

EXAMPLE 20

In a manner analogous to that described in Example 12, 2.7 g of5-butyryl-6-chloro-1-methyl-benzimidazle-2-methanol are oxidised with2.5 g of potassium permanganate to give5-butyryl-6-chloro-1-methyl-benzimidazole-2-carboxylic acid with amelting point of 90° (decomposition).

EXAMPLE 21

15.7 g of 2-methyl-4-methylamino-5-nitro-valerophenone in 180 ml ofmethanol are treated with 2 g of Raney nickel and hydrogenated undernormal pressure and at 20°-35°. After 4.2 l of hydrogen have been takenup, a solution of 9.12 g of glycollic acid in 50 ml of methanol isadded, under nitrogen, the catalyst is filtered off and the filtrate isevaporated to dryness. The residue is heated to 130° for 90 minutes, undnitrogen, and after cooling is dissolved in 100 ml of 2 N hydrochloricacid. The solution is filtered through diatomaceous earth, the filtrateis rendered alkaline and extracted with methylene chloride and theextract is washed twice with water dried over sodium sulphate andevaporated. The residue is recrystallised from 100 ml of ethyl acetate.This gives 1 dimethyl-5-valeryl-benzimidazole-2-methanol with a meltingpoint of 125°.

The starting material can be prepared as follows:

150 ml of a 33% strength aqueous solution of methylamine are poured over17.5 g of crude mononitro-4-chloro-2-methylbutyrophenone (containingabout 50% of 4-chloro-2-methyl-5-nitro-butyrophenone) and, after leavingto stand for 4 hours at room temperature, the mixture is evaporated todryness. The residue is dissolved in 100 ml of warm 2 N hydrochloricacid and the solution is rendered alkaline with sodium carbonatesolution and extracted three times with methylene chloride. The extractsare washed twice with water, dried over sodium sulphate and evaporated.Crude 2-methyl-4-methylamino-5-nitro-valerophenone, which remainsbehind, is recrystallised from cyclohexane/petroleum ether and thenmelts at 72°-77°.

EXAMPLE 22

In a manner analogous to that described in Example 12, 4.7 g of1,6-dimethyl-5-valeryl-benzimidazole-2-methanol are oxidised with 4.5 gof potassium permanganate to give1,6-dimethyl-5-valeryl-benzimidazole-2-carboxylic acid with a meltingpont>88° (decomposition).

EXAMPLE 23

In a manner analogous to that described in Example 21,1-ethyl-5-butyryl-6-methyl-benzimidazole-2-methanol with a melting pointof 152°-154° can be prepared starting from crudemononitro-4-chloro-2-methyl-butyrophenone (containing about 75% of4-chloro-2-methyl-5-nitro-butyrophenone) via4-ethylamino-2-methyl-5-nitro-butyrophenone with a melting point of118°-121°.

EXAMPLE 24

In a manner analogous to that described in Example 12, 5.2 g of1-ethyl-5-butyryl-6-methyl-benzimidazole-2-methanol can be oxidised with4.5 g of potassium permanganate to give1-ethyl-5-butyryl-6-methyl-benzimidazole-2-carboxylic acid with amelting point>80° (decomposition).

EXAMPLE 25

In a manner analogous to that described in Example 15,5-acetyl-1-n-butyl-benzimidazole-2-methanol with a melting point of121°-124° can be prepared starting from 4-chloro-3-nitroacetophenone via4-butylamino-3nitro-acetophenone with a melting point of 69°-71°.

EXAMPLE 26

In a manner analogous to that described in Example 12, 4.9 g of5-acetyl-1-n-butyl-benzimidazole-2-methanol can be oxidised with 4.5 gof potassium permanganate to give5-acetyl-1-n-butyl-benzimidazole-2-carboxylic acid with a meltingpoint>75° (decomposition).

EXAMPLE 27

In a manner analogous to that described in Example 21,1-n-butyl-5-butyryl-6-methyl-benzimidazole-2-methanol with a meltingpoint of 78°-81° is obtained starting from crudemononitro-4-chloro-2-methyl-butyrophenone (containing about 50% of4-chloro-2-methyl-5-nitro-butyrophenone) via4-butylamino-2-methyl-5-nitro-butyrophenone with a melting point of80°-82°.

EXAMPLE 28

In a manner analogous to that described in Example 12, 4.4 g of1-n-butyl-5-butyryl-6-methyl-benzimidazole-2-methanol can be oxidised to1-n-butyl-5-butyryl-6-methyl-benzimidazle-2-carboxylic acid with amelting point>70° (decomposition).

EXAMPLE 29

2.5 g of 5-butyryl-6-methyl-benzimidazole-2-carboxylic acid aredissolved in 100 ml of 0.1 N sodium hydroxide solution and the solutionis treated with 14.5 g of sodium carbonate. 38 g of triethyloxoniumtetrafluoborate are added in portions, in the course of 10 minutes, tothe resulting suspension. The mixture is stirred for a further 30minutes and extracted with ethyl acetate and the extract is washed twicewith water, dried over sodium sulphate and evaporated to dryness. Theevaporation residue is chromatographed on 100 g of silica gel usingchloroform as the eluant. This gives ethyl5-butyryl-6-methyl-benzimidazole-2-carboxylate with a melting point of142°-144°.

EXAMPLE 30

A mixture of 2.5 g of 5-butyryl-6-methyl-benzimidazole-2-carboxylicacid, 1.91 g of dimethylformamide diethyl acetal and 25 ml ofacetonitrile is left to stand for 2 days at room temperature, with theexclusion of moisture and with occasional shaking. The acetonitrile isstripped off under reduced pressure, the residue is partitioned betweenethyl acetate and sodium bicarbonate solution, the neutral phase iswashed with water and evaporated and the residue is chromatographed onaluminium oxide using chloroform/ethanol (9:1) and ethyl5-butyryl-6-methyl-benzimidazole-2-carboxylate with a melting point of142°-144° is obtained.

EXAMPLE 31

19.1 g of 5-butyryl-6-methyl-benzimidazole-2-carboxylic acid are added,in the course of 5 minutes, to a mixture of 62.9 g of diethylpyrocarbonate, 100 ml of triethylamine and 500 ml of acetonitrile, whilestirring. The mixture is stirred further, first for 1 hour at roomtemperature and then for 6 hours at the boil, and evaporated to drynessunder reduced pressure, the residue is taken up in ethyl acetate, thesolution is washed with sodium bicarbonate solution and twice withwater, dried over sodium sulphate and evaporated and the residue isrecrystallised from ethyl acetate/methylene chloride. This gives ethyl5-butyryl-6-methyl-benzimidazole-2-carboxylate with a melting point of146°-147°.

EXAMPLE 32

22.2 g of 4-amino-2-methyl-5-nitro-butyrophenone are dissolved in 230 mlof methanol, treated with 2 g of Raney nickel and hydrogenated at15°-25° under normal pressure until 4.9 liters of hydrogen have beentaken up. 20.8 g of ethoxyacetic acid are added, under nitrogen, thecatalyst is filtered off, the filtrate is evaporated under reducedpressure and the residue is heated at 130° for 3 hours. After cooling,it is dissolved in 200 ml of 2 N hydrochloric acid, the solution iswashed twice with ethyl acetate, rendered alkaline in the cold withsodium carbonate and extracted twice with ethyl acetate, the extractsare dried over sodium sulphate and evaporated and the residue ischromatographed on 300 g of silica gel. An initial fraction is firsteluted with 1,200 ml of chloroform and2-ethoxymethyl-5-butyryl-6-methyl-benzimidazole is then eluted with1,200 ml of chloroform/ethanol (24:1).

EXAMPLE 33

15 g of potassium permanganate are added to a solution, which has beencooled to 10°, of 18.9 g of2-ethoxymethyl-5-butyryl-6-methyl-benzimidazole in 380 ml of acetone,9.5 ml of pyridine and 5.7 ml of water, while stirring. The mixture isstirred for 1 hour while cooling with ice and for 40 hours at roomtemperature and filtered, the filtrate is evaporated to dryness underreduced pressure, the residue is taken up in ethyl acetate and theresulting solution is washed successively with sodium bicarbonatesolution, which has been buffered to pH 6, and twice with water, driedover sodium sulphate and evaporated under reduced pressure. The residueis then taken up in 30 ml of warm ethyl acetate, the solution is left tostand overnight and crystalline ethyl5-butyryl-6-methylbenzimidazole-2-carboxylate with a melting point of137°-139° is filtered off. Further product with a melting point of129°-132° can be obtained from the mother liquor. Recrystallisation fromethyl acetate/methylene chloride raises the melting point to 146°-147°.

EXAMPLE 34

6.0 g of 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylate acid areintroduced, in the course of 15 minutes, into a mixture of 150 ml ofacetonitrile, 15 ml of triethylamine and 18.5 g of diethylpyrocarbonate, while stirring at room temperature. The mixture is leftto stand overnight, the acetonitrile is stripped off under reducedpressure, the residue is taken up in ethyl acetate and the resultingsolution is washed with water, dried over sodium sulphate and evaporatedto dryness. Ethyl 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylate,which is initially obtained as an oil but soon crystallises, is filteredoff. When recrystallised from ethyl acetate/cyclohexane, it melts at106°-108°.

EXAMPLE 35

In a manner analogous to that described in Example 31, ethyl5-butyryl-1-methyl-benzimidazole-2-carboxylate with a melting point of115°-117° is obtained starting from 10.1 g of5-butyryl-1-methyl-benzimidazole-2-carboxylic acid and 20 g of diethylpyrocarbonate.

EXAMPLE 36

In a manner analogous to that described in Example 32,2-ethoxymethyl-5-butyryl-1,6-dimethyl-benzimidazole with a melting pointof 46°-47° is obtained starting from 23.6 g of2-methyl-4-methylamino-5-nitro-butyrophenone and 10.4 g of ethoxyaceticacid.

EXAMPLE 37

16.5 ml of half-concentrated hydrochloric acid are poured over 23.4 g of3,4-diamino-benzophenone and 12.7 g of glycollic acid and the mixture isheated at 130°-140° for 105 minutes. It is poured, while still hot, into1,500 ml of ice water, the resulting mixture is rendered alkaline withconcentrated ammonia solution and stirred for 60 minutes at roomtemperature and the precipitate is filtered off with suction. Thematerial on the suction filter is boiled with ethyl acetate, the mixtureis cooled and the product is again filtered off with suction. This gives5(6)-benzoyl-benzimidazole-2-methanol with a melting point of 226°-227°.

The starting material can be obtained starting from 20.8 g of4-chloro-3-nitro-benzophenone by warming for 15 hours with 20 g ofammonia, dissolved in 290 g of methanol and 52 g of sulpholane, to 125°in a bomb tube and hydrogenating the 4-amino-3-nitro-benzophenone, whichis thus obtainable, under normal pressure in methanol and in thepresence of Raney nickel. The product melts at 80°-83°.

EXAMPLE 38

4 g of 5(6)-benzoyl-benzimidazole-2-methanol are dissolved in 180 ml ofacetone and 55 ml of water with gentle warming and oxidised with 2.8 gof potassium permanganate, dissolved in 40 ml of water, in a manneranalogous to that described in Example 10, to give5(6)-benzoyl-benzimidazole-2-carboxylic acid.5-Benzoyl-1-methyl-benzimidazole-2-carboxylic acid can also be preparedin an analogous manner.

EXAMPLE 39

In a manner analogous to that described in Example 37,5-benzoyl-1-methyl-benzimidazole-2-methanol with a melting point of168°-172° is obtained starting from 13.2 g of3-amino-4-methylamino-benzophenone, 6.6 g of glycollic acid and 9.24 mlof half-concentrated hydrochloric acid. This product can be furtherpurified on 30 times the amount of silica gel using ethylacetate/acetone (7:3) as the eluant and then melts at 176°.

The starting material can be prepared as follows:

11 g of 4-chloro-3-nitro-benzophenone, 20 g of methylamine, 153.4 g ofmethanol and 27.5 g of sulpholane are warmed to 125° for 15 hours in aclosed vessel. The reaction solution is evaporated to dryness, theresidue is boiled thoroughly with 400 ml of 2 N hydrochloric acid for 20minutes and the precipitate is filtered off, washed with water anddissolved in methylene chloride. After drying over sodium sulphate andevaporating, 4-methylamino-3-nitro-benzophenone with a melting point of198°-201° is obtained.

15.5 g of 4-methylamino-3-nitro-benzophenone in 350 ml of methanol aretreated with 3 g of Raney nickel and hydrogenated at 20°-25° undernormal pressure. After 3.8 liters of hydrogen have been taken up, thecatalyst is filtered off and the filtrate is evaporated to dryness underreduced pressure. 3-Amino-4-methylamino-benzophenone crystallises ongrinding and after filtering off with suction and drying this melts at127°-130°.

EXAMPLE 40

22 g of 2-methoxy-4-methylamino-5-nitro-butyrophenone are dissolved in250 ml of methanol, treated with 2 g of Raney nickel and hydrogenated at35°-40° under normal pressure. After 5.9 liters of hydrogen have beentaken up, a solution of 12.9 g of glycollic acid in 20 ml of methanol isadded, under nitrogen, the catalyst is filtered off, the filtrate isevaporated to dryness and the residue is heated at 150° for 1 hour. Itis allowed to cool and dissolved in 100 ml of 2 N hydrochloric acid, thesolution is filtered, the filtrate is rendered alkaline with sodiumhydroxide solution and extracted with 2,000 ml of methylene chloride,the extract is highly concentrated under reduced pressure and treatedwith ethyl acetate, all of the methylene chloride is stripped off, theresidual mixture is cooled and the precipitate is filtered off andwashed with ethyl acetate/petroleum ether.5-Butyryl-6-methoxy-1-methyl-benzimidazole-2-methanol melts at179°-184°.

The starting material can be prepared as follows:

Sodium methylate freshly prepared from 0.23 g of sodium and 25 ml ofmethanol is suspended, while still moist, in 10 ml ofhexamethylphosphoric acid triamide, under nitrogen, and the suspensionis treated with 2.45 g of 2-chloro-4-methylamino-5-nitro-butyrophenone.An exothermic reaction starts. The mixture is stirred for a further 2hours at room temperature, treated with water and extracted with ethylacetate. The extract is washed with water, dried over sodium sulphateand evaporated and the residue is recrystallised from ethyl acetate.2-Methoxy-4-methylamino-5-nitro-butyrophenone melts at 165°-166°.

EXAMPLE 41

In a manner analogous to that described in Example 12, 5.2 g of5-butyryl-6-methoxy-1-methyl-benzimidazole-2-methanol are oxidised with4.5 g of potassium permanganate to give5-butyryl-6-methoxy-1-methyl-benzimidazole-2-carboxylic acid with amelting point above 85° (decomposition)

EXAMPLE 42

A solution of 15.0 g of crude5-amino-2-methyl-4-methylamino-cyclopropylcarbonylbenzene in 200 ml ofabsolute methanol is treated with 6.25 g of glycollic acid. The mixtureis then stirred at 35° for 15 minutes, under a nitrogen atmosphere, andevaporated to dryness under reduced pressure. The crystalline residue isheated to 130° and stirred at this temperature for three hours. The meltis cooled and dissolved in 300 ml of 2 N hydrochloric acid. The acidsolution is rendered alkaline with 2 N sodium bicarbonate solution. Theoil which has separated out is extracted with methylene chloride and theorganic extract is washed with water, dried over magnesium sulphate andconcentrated to dryness under reduced pressure. The residue ischromatographed on 400 g of silica gel using methylene chloride/methanol(9:1) as the eluant. 700 ml fractions are collected.5-Cyclopropylcarbonyl-1,6-dimethylbenzimidazole-2-methanol is containedin fractions 3-8 and these are combined and evaporated under reducedpressure. When crystallised from ethyl acetate, the compound melts at143°-144°.

The starting material can be prepared as follows:

A suspension of 428 g of 3-chloro-toluene and 174.6 g of powderedaluminium chloride is treated with 124 g of cyclopropanecarboxylic acidchloride in the course of one hour. The reaction mixture is then heatedto 50° for one hour and poured onto 1,000 g of ice. The oil which hasseparated out is extracted with 1,000 ml of ether. The organic phase,which has been separated off, is washed with twice 200 ml of 2 Nhydrochloric acid, 200 ml of 2 N sodium carbonate solution and water,dried over magnesium sulphate and concentrated to dryness. The residue,which is thus obtained, is distilled. This gives a mixture of4-chloro-2-methyl-cyclopropylcarbonyl-benzene and the isomeric2-chloro-4-methyl-cyclopropylcarbonyl-benzene in a ratio of 2:1. Boilingpoint 100°-102°/0.05 mmHg.

123 g of a mixture of isomers comprising4-chloro-2-methyl-cyclopropylcarbonyl-benzene and2-chloro-4-methyl-cyclopropylcarbonyl-benzene are added dropwise to 538ml of concentrated sulphuric acid, which has been cooled to -20° to-25°, while stirring well. The solution is treated, at -20° to -25°, inthe course of 30 minutes with a mixture of 31.3 ml of 100% strengthnitric acid (d: 1.52) and 101.2 ml of concentrated sulphuric acid andthe mixture is then stirred for a further 10 minutes, during which timethe temperature rises to -10°. The mixture is poured into 6,000 ml ofwater and the oil which has separated out is extracted with 2,000 ml ofether. The organic phase is washed twice with water, then twice with, ineach case, 300 ml of 2 N potassium bicarbonate solution and again withwater, dried over magnesium sulphate and evaporated. The residue, whichis an oil, consits of a mixture, about 2/3 of which comprises4-chloro-2-methyl-5-nitro-cyclopropylcarbonyl-benzene and whichadditionally contains an isomer, probably2-chloro-4-methyl-5-cyclopropyl-carbonyl-benzene, and this mixture isfurther reacted without further purification.

127 g of this mixture of isomers which contains4-chloro-2-methyl-5-nitro-cyclopropylcarbonyl-benzene in addition to2-chloro-4-methyl-5-nitro-cyclopropylcarbonyl-benzene are treated with600 ml of a 33% strength solution of methylamine in ethanol. The oilystarting material dissolves and a yellow coloration develops. Themixture is left to stand for 30 minutes at room temperature and is thenconcentrated to dryness under reduced pressure. The residue is treatedwith 2,000 ml of methylene chloride, ice and sodium carbonate, themixture is shaken and the organic phase is separated off. This is washedwith water, dried over magnesium sulphate and evaporated to drynessunder reduced pressure. The residue is crystallised from ethyl acetate.2-Methyl-4-methylamino-5-nitro-cyclopropylcarbonyl-benzene melts at144°-148°.

After adding 2.8 g of Raney nickel, a solution of5-nitro-2-methyl-4-methylamino-cyclopropylcarbonyl-benzene in 280 ml ofmethanol is hydrogenated for 8 hours at 25° and under normal pressure.After the hydrogenation has ended, the catalyst is filtered off under anitrogen atmosphere and the methanolic solution of unstable5-amino-2-methyl-4-methylaminocyclopropylcarbonyl-benzene is immediatelyreacted further.

EXAMPLE 43

A solution of 1.6 g of5-cyclopropyl-carbonyl-6-methylbenzimidazole-2-methanol in 93 ml ofacetone is diluted with 72 ml of water, while stirring. This solution istreated with 1.6 g of potassium permanganate and stirred at roomtemperature for 15 hours. The suspension is then concentrated underreduced pressure to about 70 ml and filtered through a layer ofdiatomaceous earth. The material on the filter is then washed with 40 mlof water and the aqueous filtrate is acidified with 2 N hydrochloricacid. The precipitate formed is filtered off, washed with 10 ml ofwater, suspended in 10 ml of cold methanol and filtered off again.5-Cyclopropylcarbonyl-6-methyl-benzimidazole-2-carboxylic acid melts at89°-92° (decomposition).

EXAMPLE 44

A solution of 5.0 g of 5-butyryl-1,6-dimethyl-benzimidazole-2-methanolin 100 ml of methylene chloride is treated with 2.36 g of acetylchloride, stirred for one hour at room temperature and then treated with5 ml of triethylamine. The mixture is stirred for a further 30 minutesand extracted by shaking with sodium bicarbonate solution and twice withwater and the extracts are dried over sodium sulphate and evaporated.This gives 2-acetoxymethyl-5-butyryl-1,6-dimethyl-benzimidazole with amelting point of 95.5°-96°.

EXAMPLE 45

27.8 g of 2-methyl-4-methylamino-5-nitro-oenanthophenone, dissolved in300 ml of methanol, are treated with 9 g of Raney nickel andhydrogenated at 20° to 25° under normal pressure until 6.8 liters ofhydrogen have been taken up. The hydrogenation solution is treated,under nitrogen, with a solution of 15 g of glycollic acid in 50 ml ofmethanol, the catalyst is filtered off and the filtrate is evaporatedunder reduced pressure. The evaporation residue is heated at 130° for 90minutes, under nitrogen, and after cooling is dissolved in 2 Nhydrochloric acid, the solution is filtered and the filtrate is renderedalkaline with concentrated sodium hydroxide solution and extracted withmethylene chloride. The organic phases are collected, washed twice withwater, dried over sodium sulphate and evaporated. This gives1,6-dimethyl-5-oenanthylbenzimidazole-2-methanol with a melting point of93°-95°.

The starting material can be prepared as follows:

60.6 g of 4-chloro-2-methyl-benzonitrile, dissolved in 60 ml of diethylether, are added dropwise to a boiling solution of n-hexyl-magnesiumbromide, prepared from 12.1 g of magnesium turnings and 82.5 g of1-bromohexane in 125 ml of diethyl ether. The reaction mixture is heatedto the boil for 5 hours. After cooling, 150 ml of 4 N hydrochloric acidare added dropwise. The mixture is stirred for a further 60 minutes andleft to stand overnight, the ether phase is separated off, the aqueousphase is washed with ether, the combined ether phases are washed withwater, dried over sodium sulphate and evaporated and the residue isdistilled. 4-Chloro-2-methyl-oenanthophenone passes over at a boilingpoint/10 mm Hg of 165°-170°.

67.7 g of 4-chloro-2-methyl-oenanthophenone are dissolved in 285 ml ofsulphuric acid, which has been cooled to -15° to -10°, and the solutionis treated dropwise, in the course of 15 minutes, with a mixture of 16.3ml of fuming nitric acid and 53 ml of sulphuric acid. The mixture isstirred for a further 30 minutes at -15°, poured into 1,500 ml of icewater and extracted with methylene chloride. The organic phase is washedsuccessively with water, sodium bicarbonate solution and twice withwater, dried over sodium sulphate and evaporated.4-Chloro-2-methyl-5-nitro-oenanthophenone can be reacted further withoutfurther purification.

78.8 g of 4-chloro-2-methyl-5-nitro-oenanthophenone are dissolved in 600ml of ethanol and the solution is treated with 200 ml of a 33% strengthaqueous solution of methylamine, heated on a water bath for 60 minutesand left to stand overnight at room temperature. The mixture isevaporated to dryness and the residue is heated with 300 ml of 2 Nhydrochloric acid to 80° to 90° for 60 minutes and the mixture is cooledto 10° to 15° by adding ice, the precipitate is filtered off and takenup in methylene chloride, the solution is dried over sodium sulphate andagain evaporated to dryness, the residue is ground with 200 ml ofpetroleum ether (60°-80°) and2-methyl-4-methylamino-5-nitro-oenanthophenone with a melting point of77°-79° is filtered off.

EXAMPLE 46

11.6 g of ethyl5-(1-hydroxybutyl)-1,6-dimethyl-2-ethoxy-methylbenzimidazole-2-carboxylateare dissolved in 400 ml of acetone and 100 ml of water and the solutionis cooled to +5° and treated with 10 g of potassium permanganate. Themixture is stirred for 2 hours at +5° and overnight at room temperature,the manganese dioxide is filtered off, the acetone is stripped from thefiltrate under reduced pressure, the residue is exhaustively extractedwith ethyl acetate and the extract is dried over sodium sulphate, highlyconcentrated under reduced pressure and ground with cyclohexane. Thisgives ethyl 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylate with amelting point of 106°-108°.

The starting material can be obtained, for example, by hydrogenating2-methyl-4-methylamino-5-nitro-butyrophenone in the presence ofpalladium on charcoal at atmospheric pressure and 25° to 50° andcondensing 3-(1-hydroxybutyl)-4-methyl-2-methylamino-aniline which canbe thus obtained, with ethoxyacetic acid in the presence of dilutedhydrochloric acid treating the reaction product, if necessary, withaqueous potassium acetate solution in order to hydrolyse any5-(1-chlorobutyl-1,6-dimethyl-2-ethoxymethyl-benzimidazole which mayhave been formed. The5-(1-hydroxybutyl)-1,6-dimethyl-2-ethoxymethylbenzimidazole can be usedwithout further purification.

EXAMPLE 47

5-Butyryl-6-hydroxy-1-methyl-benzimidazole-2-carboxylic acid,5-butyryl-6-hydroxy-1-methyl-benzimidazole-2-methanol,1,6-dimethyl-5-(4-methylthiobutyryl)-benzimidazole-2-methanol5-isobutyryl-1,6-dimethyl-benzimidazole-2-methanol, m.p. 148°-150°,5-isobutyryl-1,6-dimethyl-benzimidazole-2-carboxylic acid,5-propionyl-1,6-dimethyl-benzimidazole-2-methanol, m.p. 139°-140° C.,5-(2-methylbutyryl)-1,6-dimethyl-benzimidazole-2-methanol, m.p. 158°,5-isovaleryl-1,6-dimethyl-benzimidazole-2-methanol, m.p. 142°-142.5°,5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylic acid isopropyl ester,m.p. 90°-91°, 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylic acid(1-dimethylamino)-2-propyl ester,5-propionyl-1,6-dimethylbenzimidazole-2-carboxylic acid ester and5-butyryl-1,6-dimethyl-2-(2-dimethylaminoethoxymethyl)-benzimidazole canalso be prepared in a manner analogous to that described in Examples10-45.

EXAMPLE 48

A 2% strength aqueous solution, which is suitable for inhalation, of thesodium salt of 5-butyryl-6-methyl-benzimidazole-2-carboxylic acid can beprepared as follows:

    ______________________________________                                        Composition (for 100 ml)                                                      ______________________________________                                        Sodium salt of 5-butyryl-6-methyl-benzimidazole-                              2-carboxylic acid          2.000 g                                            Dissodium salt of ethylenediaminetetraacetic acid                             (stabiliser)               0.010 g                                            Benzalkonium chloride (preservative)                                                                     0.010 g                                            Distilled water            ad 100 ml                                          ______________________________________                                    

The sodium salt of 5-butyryl-6-methyl-benzimidazole-2-carboxylic acid isdissolved in freshly distilled water and the solution is treated withthe disodium salt of ethylenediaminetetraacetic acid and thebenzalkonium chloride (mixture of alkyl-dimethyl-benzyl-ammoniumchlorides in which alkyl contains from 8 to 18 carbon atoms). After thecomponents have completely dissolved, the resulting solution is made upto a volume of 100 ml with water, filled into a container and sealedgastight.

EXAMPLE 49

A 2% strength aqueous solution, which is suitable for inhalation, of thesodium salt of 5-butyryl-1,6-dimethylbenzimidazole-2-carboxylic acid canbe prepared as follows:

    ______________________________________                                        Composition (for 100 ml)                                                      ______________________________________                                        Sodium salt of 5-butyryl-1,6-dimethyl-benzimidazole-                          2-carboxylic acid           2.000 g                                           Disodium salt of ethylenediaminetetraacetic acid                              (stabiliser)                0.010 g                                           Benzalkonium chloride (preservative)                                                                      0.010 g                                           Distilled water             ad 100 ml                                         ______________________________________                                    

The sodium salt of 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylicacid is dissolved in freshly distilled water and the solution is treatedwith the disodium salt of ethylenediaminetetraacetic acid and thebenzalkonium chloride (mixture of alkyl-dimethyl-benzyl-ammoniumchlorides in which alkyl contains from 8 to 18 carbon atoms). After thecomponents have completely dissolved, the resulting solution is made upto a volume of 100 ml with water, filled into a container and sealedgas-tight.

2% strength aqueous inhalation solutions of the sodium salt of5(6)-valeryl-benzimidazole-2-carboxylic acid,5-acetyl-6-methyl-benzimidazole-2-carboxylic acid,6-methyl-5-propionylbenzimidazole-2-carboxylic acid,6-methyl-5-valeryl-benzimidazole-2-carboxylic acid,5(6)-butyryl-benzimidazole-2-carboxylic acid,5-butyryl-6-methoxy-benzimidazole-2-carboxylic acid,5-butyryl-6-chloro-benzimidazole-2-carboxylic acid,5-cyclopropylcarbonyl-6-methyl-2-benzimidazole-2-carboxylic acid,5-cyclohexylcarbonyl-6-methyl-2-benzimidazole-2-carboxylic acid,5-(4-methoxybutyryl)-6-methyl-2-benzimidazole-2-carboxylic acid,6-methyl-5-(4-methylthiobutyryl)-benzimidazole-2-carboxylic acid,6-methyl-5-(4-methylsulphinylbutyryl)-benzimidazole-2-carboxylic acid,6-methyl-5-(4-phenylthiobutyryl)-benzimidazole-2-carboxylic acid,6-methyl-5-(4-phenylsulphinylbutyryl)-benzimidazole-2-carboxylic acid,5-acetyl-1-methyl-benzimidazole-2-carboxylic acid,5-butyryl-1-methyl-benzimidazole-2-carboxylic acid,5-butyryl-6-chloro-1-methyl-benzimidazole-2-carboxylic acid,1,6-dimethyl-5-valerylbenzimidazole-2-carboxylic acid,1-ethyl-5-butyryl-6-methylbenzimidazole-2-carboxylic acid,5-acetyl-1-butyl-benzimidazole-2-carboxylic acid,1-butyl-5-butyryl-benzimidazole-2-carboxylic acid,5(6)-benzoyl-benzimidazole-2-carboxylic acid,5-cyclopropylcarbonyl-1,6-dimethyl-benzimidazole-2-carboxylic acid and5-butyryl-6-hydroxy-1-methyl-benzimidazole-2-carboxylic acid can beprepared in an analogous manner.

EXAMPLE 50

A 2% strength aqueous solution, which is suitable for inhalation, of5-butyryl-1,6-dimethyl-benzimidazole-2-methanol can be prepared asfollows:

    ______________________________________                                        Composition (for 100 ml)                                                      ______________________________________                                        5-Butyryl-6-methyl-benzimidazole-2-methanol                                                              2.000 g                                            Disodium salt of ethylenediaminetetraacetic                                   acid (stabiliser)          0.010 g                                            Benzalkonium chloride (preservative)                                                                     0.010 g                                            Distilled water            ad 100 ml                                          ______________________________________                                    

The 5-butyryl-1,6-dimethyl-benzimidazole-2-methanol is dissolved infreshly distilled water with the addition of the solubilising agent, forexample polyethylene glycol, and the solution is treated with thedisodium salt of ethylenediaminetetraacetic acid and the benzalkoniumchloride (mixture of alkyl-dimethyl-benzyl-ammonium chlorides in whichalkyl contains from 8 to 18 carbon atoms). After the components havecompletely dissolved, the resulting solution is made up to a volume of100 ml with water, filled into a container and sealed gas-tight.

2% strength aqueous inhalation solutions of5-butyryl-6-methyl-benzimidazole-2-methanol,5(6)-valeryl-benzimidazole-2-methanol,6-methyl-5-valeryl-benzimidazole-2-methanol,5(6)-butyryl-benzimidazole-2-methanol,5-acetyl-1-methyl-benzimidazole-2-methanol,5-butyryl-1-methyl-benzimidazole-2-methanol,5-butyryl-6-chloro-1-methyl-benzimidazole-2-methanol,1,6-dimethyl-5-valeryl-benzimidazole-2-methanol,1-ethyl-5-butyryl-6-methyl-benzimidazole-2-methanol,5-acetyl-1-butyl-benzimidazole-2-methanol,1-butyl-5-butyryl-6-methyl-benzimidazole-2-methanol,5-benzoyl-benzimidazole-2-methanol, 5-benzoyl-benzimidazole-2-methanol,5-butyryl-6-methoxy-1-methyl-benzimidazole-2-methanol,1,6-dimethyl-5-oenanthyl-benzimidazole-2-methanol,5-cyclopropylcarbonyl-1,6-dimethyl-benzimidazole-2-methanol,2-ethoxymethyl-5-butyryl-6-methyl-benzimidazole,2-ethoxymethyl-5-butyryl-1,6-dimethyl-benzimidazole,2-acetoxymethyl-5-butyryl-1,6-dimethyl-benzimidazole,5-butyryl-6-hydroxy-1-methyl-benzimidazole-2-methanol,1,6-dimethyl-5-(4-methylthiobutyryl)-benzimidazole-2-methanol,5-butyryl-1,6-dimethyl-2-(2-dimethylaminoethoxy-methyl)-benzimidazole,ethyl 5-butyryl-6-methyl-benzimidazole-2-carboxylate, ethyl5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylate, ethyl5-butyryl-1-methyl-benzimidazole-2-carboxylate and methyl5-butyryl-6-methyl-benzimidazole-2-carboxylate can be prepared in ananalogous manner.

EXAMPLE 51

Capsules containing 0.025 g of5-butyryl-6-methylbenzimidazole-2-carboxylic acid, which are suitablefor insufflation, can be prepared as follows:

    ______________________________________                                        Composition (for 1,000 capsules)                                              ______________________________________                                        5-Butyryl-6-methyl-benzimidazole-2-carboxylic acid                                                        25.00 g                                           Ground lactose              25.00 g                                           ______________________________________                                    

The 5-butyryl-6-methyl-benzimidazole-2-carboxylic acid and the lactose(very finely ground) are mixed together well. The resulting powder isthen sieved and 0.05 g portions are filled into gelatin capsules.

EXAMPLE 52

Capsules containing 0.025 g of5-butyryl-1,6-dimethylbenzimidazole-2-carboxylic acid, which aresuitable for insufflation, can be prepared as follows:

    ______________________________________                                        Composition (for 1,000 capsules)                                              ______________________________________                                        5-Butyryl-1,6-dimethyl-benzimidazole-2-                                       carboxylic acid           25.00 g                                             Ground lactose            25.00 g                                             ______________________________________                                    

The 5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylic acid and thelactose (very finely ground) are mixed together well. The resultingpower is then sieved and 0.05 g portions are filled into gelatinecapsules.

Insufflation capsules containing, in each case, 0.025 g of5(6)-valery-benzimidazole-2-carboxylic acid,5-acetyl-6-methyl-benzimidazole-2-carboxylic acid,6-methyl-5-propionylbenzimidazole-2-carboxylic acid,6-methyl-5-valeryl-benzimidazole-2-carboxylic acid,5(6)-butyryl-benzimidazole-2-carboxylic acid,5-butyryl-6-methoxy-benzimidazole-2-carboxylic acid,5-butyryl-6-chloro-benzimidazole-2-carboxylic acid,5-cyclopropylcarbonyl-6-methyl-benzimidazole-2-carboxylic acid,5-cyclohexylcarbonyl-6-methyl-benzimidazole-2-carboxylic acid,5-(4-methoxybutyryl)-6-methyl-benzimidazole-2-carboxylic acid,6-methyl-5-(4-methylthiobutyryl)-benzimidazole-2-carboxylic acid,6-methyl-5-(4-methylsulphinylbutyryl)-benzimidazole-2-carboxylic acid,6-methyl-5-(4-phenylthiobutyryl)-benzimidazole-2-carboxylic acid,6-methyl-5-(4-phenylsulphinylbutyryl)-benzimidazole-2-carboxylic acid,methyl 5-butyryl-6-methyl-benzimidazole-2-carboxylate,5-butyryl-6-methyl-benzimidazole-2-methanol,5-butyryl-1,6-dimethyl-benzimidazole-2-methanol,5(6)-valeryl-benzimidazole-2-methanol,6-methyl-5-valeryl-benzimidazole-2-methanol,5(6)-butyryl-benzimidazole-2-methanol,5-acetyl-1-methyl-benzimidazole-2-methanol,5-butyryl-1-methylbenzimidazole-2-methanol,5-butyryl-6-chloro-1-methyl-benzimidazole-2-methanol,1,6-dimethyl-5-valeryl-benzimidazole-2-methanol,1-ethyl-5-butyryl-6-methyl-benzimidazole-2-methanol,5-acetyl-1-butyryl-benzimidazole-2-methanol,1-butyl-5-butyryl-6-methyl-benzimidazole-2-methanol,5-benzoyl-benzimidazole-2-methanol,5-benzoyl-1-methyl-benzimidazole-2-methanol,5-butyryl-6-methoxy-1-methyl-benzimidazole-2-methanol,5-cyclopropylcarbonyl-1,6-dimethyl-benzimidazole-2-methanol,2-ethoxymethyl-5-butyryl-6-methyl-benzimidazole,2-ethoxymethyl-5-butyryl-1,6-dimethyl-benzimidazole,2-acetoxymethyl-5-butyryl-1,6-dimethyl-benzimidazole,5-butyryl-6-hydroxy-1-methyl-benzimidazole-2-methanol,1,6-dimethyl-5-(4-methylthiobutyryl)-benzimidazole-2-methanol,5-butyryl-1,6-dimethyl-2-(2-dimethylaminoethoxymethyl)-benzimidazole,5-acetyl-1-methyl-benzimidazole-2-carboxylic acid,5-butyryl-1-methyl-benzimidazole-2-carboxylic acid,5-butyryl-6-chloro-1-methyl-benzimidazole-2-carboxylic acid,1,6-dimethyl-5-valeryl-benzimidazole-2-carboxylic acid,1-ethyl-5-butyryl-6-methyl-benzimidazole-2-carboxylic acid,5-acetyl-1-butyl-benzimidazole-2-carboxylic acid,1,6-dimethyl-5-cenanthyl-benzimidazole-2-methanol,1-butyl-5-butyryl-benzimidazole-2-carboxylic acid,5(6)-benzoylbenzimidazole-2-carboxylic acid,5-cyclopropylcarbonyl-1,6-dimethyl-benzimidazole-2-carboxylic acid,5-butyryl-6-hydroxy-1-methyl-benzimidazole-2-carboxylic acid, ethyl5-butyryl-6-methyl-benzimidazole-2-carboxylic, ethyl5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylate or ethyl5-butyryl-1-methyl-benzimidazole-2-carboxylate can also be prepared inan analogous manner.

EXAMPLE 53

Tablets containing 100 mg ofbutyryl-1,6-dimethylbenzimidazole-2-carboxylic acid or its sodium salt(active compound) can be prepared, for example, in the followingcomposition:

    ______________________________________                                        Composition             Per Tablet                                            ______________________________________                                        Active compound, for example 5-butyryl-                                       1,6-dimethyl-benzimidazole-2-carboxylic acid                                                          100 mg                                                Lactose                  50 mg                                                Wheat starch             73 mg                                                Colloidal silica         13 mg                                                Talc                     12 mg                                                Magnesium stearate       2 mg                                                                         250 mg                                                ______________________________________                                    

Preparation

The active compound is mixed with the lactose and part of the wheatstarch and with colloidal silica and the mixture is forced through asieve. A further portion of the wheat starch is mixed to a paste with 5times the amount of water on a water bath and the pulverulent mixture iskneaded with this paste until a slightly plastic mass has formed. Themass is forced through a sieve of about 3 mm mesh width and dried andthe dry granules are again forced through a sieve. The remaining wheatstarch, the talc and magnesium stearate are then mixed in. The resultingmixture is pressed to give 250 mg tablets with a breaking groove (orgrooves).

In an analogous manner it is also possible to prepare tabletscontaining, in each case, 100 mg of one of the compounds listed belowand these compounds can also be used in the form of salts which can beused pharmaceutically, such as acid addition salts, for example thehydrochlorides, or, in the case of carboxylic acids, salts with a base,for example sodium salts: 5-butyryl-6-methyl-benzimidazole-2-carboxylicacid, 5(6)-valeryl-benzimidazole-2-carboxylic acid,5-acetyl-6-methyl-benzimidazole-2-carboxylic acid,6-methyl-5-propionyl-benzimidazole-2-carboxylic acid,6-methyl-5-valeryl-benzimidazole-2-carboxylic acid,5(6)-butyryl-benzimidazole-2-carboxylic acid,5-butyryl-6-methoxy-benzimidazole-2-carboxylic acid,5-butyryl-6-chlorobenzimidazole-2-carboxylic acid,5-cyclopropylcarbonyl-6-methyl-benzimidazole-2-carboxylic acid,5-cyclohexylcarbonyl-6-methylbenzimidazole-2-carboxylic acid,5-(4-methoxybutyryl)-6-methylbenzimidazole-2-carboxylic acid,6-methyl-5-(4-methylthiobutyryl)-benzimidazole-2-carboxylic acid,6-methyl-5-(4-methylsulphinylbutyryl)-benzimidazole-2-carboxylic acid,6-methyl-5-(4-phenylthiobutyryl)-benzimidazole-2-carboxylic acid,6-methyl-5-(4-phenylsulphinylbutyryl)-benzimidazole-2-carboxylic acid,methyl 5 -butyryl-6-methyl-benzimidazole-2-carboxylate,5-butyryl-6-methyl-benzimidazole-2-methanol,5-butyryl-1,6-dimethyl-benzimidazole-2-methanol,5(6)-valeryl-benzimidazole-2-methanol,6-methyl-5-valeryl-benzimidazole-2-methanol,5(6)-butyryl-benzimidazole-2-methanol,5-acetyl-1-methyl-benzimidazole-2-methanol,5-butyryl-1-methyl-benzimidazole-2-methanol,5-butyryl-6-chloro-1-methyl-benzimidazole-2-methanol,1,6-dimethyl-5-valeryl-benzimidazole-2-methanol,1-ethyl-5-butyryl-6-methyl-benzimidazole-2-methanol,5-acetyl-1-butyl-benzimidazole-2-methanol,1-butyl-5-butyryl-6-methyl-benzimidazole-2-methanol,1,6-dimethyl-5-oenanthyl-benzimidazole-2-methanol,5-benzoyl-benzimidazole-2-methanol,5-benzoyl-1-methyl-benzimidazole-2-methanol,5-butyryl-6-methoxy-1-methyl-benzimidazole-2-methanol,5-cyclopropylcarbonyl-1,6-dimethyl-benzimidazole-2-methanol,2-ethoxymethyl-5-butyryl-6-methyl-benzimidazole,2-ethoxymethyl-5-butyryl-1,6-dimethyl-benzimidazole,2-acetoxymethyl-5-butyryl-1,6-dimethyl-benzimidazole,5-butyryl-6-hydroxy-1-methyl-benzimidazole-2-methanol,1,6-dimethyl-5-(4-methylthiobutyryl)-benzimidazole-2-methanol,5-butyryl-1,6-dimethyl-2-(2-dimethylaminoethoxymethyl)-benzimidazole,5-acetyl-1-methyl-benzimidazole-2-carboxylic acid,5-butyryl-1-methyl-benzimidazole-2-carboxylic acid,5-butyryl-6-chloro-1-methyl-benzimidazole-2-carboxylic acid,1,6-dimethyl-5-valeryl-benzimidazole-2-carboxylic acid,1-ethyl-5-butyryl-6 -methyl-benzimidazole-2-carboxylic acid,5-acetyl-1-butyryl-benzimidazole-2-carboxylic acid,1-butyl-5-butyryl-benzimidazole-2-carboxylic acid,5(6)-benzoyl-benzimidazole-2-carboxylic acid,5-cyclopropylcarbonyl-1,6-dimethyl-benzimidazole-2-carboxylic acid,5-butyryl-6-hydroxy-1-methyl-benzimidazole-2-carboxylic acid, ethyl5-butyryl-6-methyl-benzimidazole-2-carboxylate, ethyl5-butyryl-1,6-dimethyl-benzimidazole-2-carboxylate and ethyl5-butyryl-1-methyl-benzimidazole-2-carboxylate.

I claim:
 1. A benz-acyl-benzimidazole-2-methanol derivative of theformula: ##STR10## in which R is hydroxymethyl or etherifiedhydroxymethyl containing, as the etherified hydroxyl group, loweralkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy or di-loweralkylamino-lower alkoxy, R₁ is lower alkyl which is unsubstituted orsubstituted by lower alkoxy, lower alkylthio, lower alkylsulphinyl,lower alkylsulphonyl, phenylthio, phenylsulphinyl or phenylsulphonyl, orphenyl or phenyl-lower alkyl which are unsubstituted or substituted inthe phenyl radical by lower alkyl, lower alkoxy or halogen, or is loweralkenyl or cycloalkyl having 3 to 8 carbon atoms, R₂ is hydrogen orlower alkyl and Ph is 1,2-phenylene which contains the radical of theformula R₁ --C(═O)-- and is otherwise unsubstituted or substituted bylower alkyl, lower alkoxy, hydroxyl halogen.
 2. A compound as claimed inclaim 1, in which R is hydroxymethyl or etherified hydroxymethylcontaining, as the etherified hydroxyl group, lower alkoxy having up to4 carbon atoms or di-lower alkyl-amino-lower alkoxy having in each case,up to 4 carbon atoms in the alkyl part and the alkoxy part, R₁ is loweralkyl having up to and including 7 carbon atoms, lower alkoxy-loweralkyl, lower alkylthio-lower alkyl, loweralkylsulphinyl-lower alkyl orlower alkylsulphonyl-lower alkyl, in which the individual lower alkylradicals contain up to and including 4 carbon atoms, phenylthio-loweralkyl, phenylsulphinyl-lower alkyl or phenylsulphonyl-lower alkyl, inwhich the lower alkyl radical contains up to and including 4 carbonatoms, lower alkenyl having up to and including 5 carbon atoms,cycloalkyl having up to and including 7 carbon atoms, phenyl orphenyl-lower alkyl having up to and including 4 carbon atoms in thelower alkyl radical and being unsubstituted or substituted by loweralkyl having up to and including 4 carbon atoms, lower alkoxy having upto and including 4 carbon atoms and/or halogen having an atomic numberof up to and including 35, R₂ is hydrogen or lower alkyl having up toand including 4 carbon atoms and Ph is 1,2-phenylene which contains theradical of the formula R₁ -C(═O)-- and is otherwise unsubstituted orsubstituted by lower alkyl having up to and including 4 carbon atoms,lower alkoxy having up to and including 4 carbon atoms, hydroxyl and/orhalogen having an atomic number of up to and including
 35. 3. A compoundas claimed in claim 1, having the formula ##STR11## in which R' ishydroxymethyl or etherified hydroxymethyl containing, as the etherifiedhydroxyl group, lower alkoxy having up to 4 carbon atoms or di-loweralkyl-amino-loer alkoxy having up to 7 carbon atoms, R₁ ' is lower alkylhaving up to 7 carbon atoms, lower alkoxy-lower alkyl, loweralkylthio-lower alkyl, lower alkylsulphinyl-lower alkyl,phenylthio-lower alkyl or phenylsulphinyl-lower alkyl, in which thelower alkyl radicals contain up to and including 4 carbon atoms,cycloalkyl having up to and including 6 ring carbon atoms or phenyl, R₂' is hydrogen or lower alkyl having up to and including 4 carbon atomsand R₃ is hydrogen, lower alkyl having up to and including 4 carbonatoms, lower alkoxy having up to and including 4 carbon atoms, hydroxylor halogen having an atomic number of up to and including
 35. 4. Acompound as claimed in claim 3, in which R' is hydroxymethyl oretherified hydroxymethyl containing, as the etherified hydroxyl group,lower alkoxy having up to 4 carbon atoms, R₁ ' is lower alkyl having upto and including 7 carbon atoms, cycloalkyl having up to and including 6ring carbon atoms or phenyl, R₂ ' is hydrogen or lower alkyl having upto and including 4 carbon atoms and R₃ is hydrogen, lower alkyl havingup to and including 4 carbon atoms, lower alkoxy having up to andincluding 4 carbon atoms or halogen having an atomic number of up to andincluding
 35. 5. A compound as claimed in claim 1 being5-isobutyryl-1,6-dimethyl-benzimidazole-2-methanol.
 6. A compound asclaimed in claim 1 being a5-valeroyl-1,6-dimethyl-benzimidazole-2-methanol.
 7. A compound asclaimed in claim 1 being 1-ethyl, 5-butyryl-6-benzimidazole-2-methanol.8. A compound as claimed in claim 1 being2-ethoxy-methyl-1,6-dimethyl-benzimidazole.
 9. A compound as claimed inclaim 1 being 5-butyryl-1,6-dimethyl-benzimidazole-2-methanol.
 10. Apharmaceutical preparation containing an antiallergically effectiveamount of a compound as claimed in claim 1 together with a conventionalpharmaceutical carrier.